Prodrugs of substituted azaindoleoxoacetic piperazine derivatives

ABSTRACT

This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with azaindoleoxoacetyl piperazine derivatives. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS.

CROSS REFERENCE TO RELATED APPLICATIONS

This continuation application claims the benefit of U.S. Ser. No.14/493,515 filed Sep. 23, 2014, now pending, which in turn is acontinuation application which claims the benefit of U.S. Ser. No.14/156,718 filed Jan. 16, 2014, now abandoned, which in turn is acontinuation application which claims the benefit of U.S. Ser. No.13/858,624 filed Apr. 8, 2013, now abandoned, which in turn is acontinuation application which claims the benefit of U.S. Ser. No.13/624,222 filed Sep. 21, 2012, now abandoned, which in turn is acontinuation application which claims the benefit of U.S. Ser. No.13/473,683 filed May 17, 2012, now abandoned, which in turn is acontinuation application which claims the benefit of U.S. Ser. No.13/324,371 filed Dec. 13, 2011, now abandoned, which in turn is acontinuation application which claims the benefit of U.S. Ser. No.13/161,205 filed Jun. 15, 2011, now abandoned, which in turn is acontinuation application which claims the benefit of U.S. Ser. No.13/007,194 filed Jan. 14, 2011, now abandoned, which in turn is acontinuation application which claims the benefit of U.S. Ser. No.12/622,859 filed Nov. 20, 2009, now abandoned, which in turn is acontinuation application which claims the benefit of U.S. Ser. No.12/354,308 filed Jan. 15, 2009, now U.S. Pat. No. 7,662,823, which inturn is a continuation application which claims the benefit of U.S. Ser.No. 12/015,776 filed Jan. 17, 2008, now U.S. Pat. No. 7,501,420, whichin turn is a continuation application which claims the benefit of U.S.Ser. No. 10/969,675 filed Oct. 20, 2004, now U.S. Pat. No. 7,354,924,which in turn is a continuation application which claims the benefit ofU.S. Ser. No. 10/630,278 filed Jul. 30, 2003, now abandoned, which inturn is a continuation in Part application which claims the benefit ofU.S. Ser. No. 10/214,982 filed Aug. 7, 2002, now abandoned, which inturn is a continuation-in-part application which claims the benefit ofU.S. Ser. No. 10/038,306 filed Jan. 2, 2002, now abandoned, which inturn claims the benefit of U.S. Provisional Application Ser. Nos.60/314,406 filed Aug. 23, 2001 and 60/266,183 filed Feb. 2, 2001, nowexpired, which are herein incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention provides compounds having drug and bio-affectingproperties, their pharmaceutical compositions and method of use. Inparticular, the invention is concerned with azaindole piperazine diamidederivatives that possess unique antiviral activity. More particularly,the present invention relates to compounds useful for the treatment ofHIV and AIDS.

2. Background Art

HIV-1 (human immunodeficiency virus-1) infection remains a major medicalproblem, with an estimated 42 million people infected worldwide at theend of 2002. The number of cases of HIV and AIDS (acquiredimmunodeficiency syndrome) has risen rapidly. In 2002, ˜5.0 million newinfections were reported, and 3.1 million people died from AIDS.Currently available drugs for the treatment of HIV include ninenucleoside reverse transcriptase (RT) inhibitors or approved single pillcombinations (zidovudine or AZT (or RETROVIR®), didanosine (or VIDEX®),stavudine (or ZERIT®), lamivudine (or 3TC or EPIVIR®), zalcitabine (orDDC or HIVID®), abacavir succinate (or ZIAGEN®), Tenofovir disoproxilfumarate salt (or VIREAD®), COMBIVIR® (contains-3TC plus AZT), TRIZIVIR®(contains abacavir, lamivudine, and zidovudine); three non-nucleosidereverse transcriptase inhibitors: nevirapine (or VIRAMUNE®), delavirdine(or RESCRIPTOR®) and efavirenz (or SUSTIVA®), and eight peptidomimeticprotease inhibitors or approved formulations: saquinavir, indinavir,ritonavir, nelfinavir, amprenavir, lopinavir, KALETRA®(lopinavir andRitonavir), and Atazanavir (REYATAZ®). Each of these drugs can onlytransiently restrain viral replication if used alone. However, when usedin combination, these drugs have a profound effect on viremia anddisease progression. In fact, significant reductions in death ratesamong AIDS patients have been recently documented as a consequence ofthe widespread application of combination therapy. However, despitethese impressive results, 30 to 50% of patients ultimately failcombination drug therapies. Insufficient drug potency, non-compliance,restricted tissue penetration and drug-specific limitations withincertain cell types (e.g. most nucleoside analogs cannot bephosphorylated in resting cells) may account for the incompletesuppression of sensitive viruses. Furthermore, the high replication rateand rapid turnover of HIV-1 combined with the frequent incorporation ofmutations, leads to the appearance of drug-resistant variants andtreatment failures when sub-optimal drug concentrations are present(Larder and Kemp; Gulick; Kuritzkes; Morris-Jones et al; Schinazi et al;Vacca and Condra; Flexner; Berkhout and Ren et al; (Ref 6-14)).Therefore, novel anti-HIV agents exhibiting distinct resistancepatterns, and favorable pharmacokinetic as well as safety profiles areneeded to provide more treatment options.

Currently marketed HIV-1 drugs are dominated by either nucleosidereverse transcriptase inhibitors or peptidomimetic protease inhibitors.Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have recentlygained an increasingly important role in the therapy of HIV infections(Pedersen & Pedersen, Ref 15). At least 30 different classes of NNRTIhave been described in the literature (De Clercq, Ref 16) and severalNNRTIs have been evaluated in clinical trials. Dipyridodiazepinone(nevirapine), benzoxazinone (efavirenz) and bis(heteroaryl) piperazinederivatives (delavirdine) have been approved for clinical use. However,the major drawback to the development and application of NNRTIs is thepropensity for rapid emergence of drug resistant strains, both in tissuecell culture and in treated individuals, particularly those subject tomonotherapy. As a consequence, there is considerable interest in theidentification of NNRTIs less prone to the development of resistance(Pedersen & Pedersen, Ref 15).

Several indole derivatives including indole-3-sulfones, piperazinoindoles, pyrazino indoles, and 5H-indolo[3,2-b][1,5]benzothiazepinederivatives have been reported as HIV-1 reverse transciptase inhibitors(Greenlee et al, Ref 1; Williams et al, Ref 2; Romero et al, Ref 3; Fontet al, Ref 17; Romero et al, Ref 18; Young et al, Ref 19; Genin et al,Ref 20; Silvestri et al, Ref 21). Indole 2-carboxamides have also beendescribed as inhibitors of cell adhesion and HIV infection (Boschelli etal, U.S. Pat. No. 5,424,329, Ref 4). Finally, 3-substituted indolenatural products (Semicochliodinol A and B, didemethylasterriquinone andisocochliodinol) were disclosed as inhibitors of HIV-1 protease(Fredenhagen et al, Ref 22). Other indole derivatives exhibitingantiviral activity useful for treating HIV are disclosed in PCT WO00/76521 (Ref 93). Also, indole derivatives are disclosed in PCT WO00/71535 (Ref 94).

Structurally related aza-indole amide derivatives have been disclosedpreviously (Kato et al, Ref 23; Levacher et al, Ref 24; Dompe Spa,WO-09504742, Ref 5(a); SmithKline Beecham PLC, WO-09611929, Ref 5(b);Schering Corp., US-05023265, Ref 5(c)). However, these structures differfrom those claimed herein in that they are aza-indole mono-amide ratherthan unsymmetrical aza-indole piperazine diamide derivatives, and thereis no mention of the use of these compounds for treating viralinfections, particularly HIV. Other azaindoles have been also disclosedby Wang et al, Ref 95. Indole and azaindole piperazine containingderivatives have been disclosed in four different PCT and issued U.S.patent applications (Reference 93-95, 106). Nothing in these referencescan be construed to disclose or suggest the novel compounds of thisinvention and their use to inhibit HIV infection.

REFERENCES CITED Patent Documents

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SUMMARY DESCRIPTION OF THE INVENTION

The present invention comprises compounds of Formula I, orpharmaceutically acceptable salts thereof, which are effective antiviralagents, particularly as inhibitors of HIV.

A first embodiment of a first aspect of the invention are compounds ofFormula I, including pharmaceutically acceptable salts thereof,

wherein:Q is selected from the group consisting of:

R¹, R², R³, and R⁴, are independently selected from the group consistingof hydrogen, halogen, cyano, nitro, COOR⁵⁶, XR⁵⁷, C(O)R⁷, C(O)NR⁵⁵R⁵⁶,B, D, and E with the proviso that at least one of R¹-R⁴ is selected fromB or E;wherein — represents a carbon-carbon bond or does not exist;m is 1 or 2;R⁵ is hydrogen or (CH₂)_(n)CH₃, —C(O)(CH₂)_(n)CH₃, —C(O)O(CH₂)_(n)CH₃,—C(O) (CH₂)_(n)N(CH₃)₂ wherein n is 0-5;R⁶ is 0 or does not exist;A is selected from the group consisting of C₁₋₆alkoxy, aryl andheteroaryl; in which said aryl is phenyl or napthyl; said heteroaryl isselected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl,triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl,benzofuranyl, benzothienyl, benzoimidazolyl and benzothiazolyl; and saidaryl or heteroaryl is optionally substituted with one or two of the sameor different members selected from the group consisting of amino, nitro,cyano, hydroxy, C₁₋₆alkoxy, —C(O)NH₂, C₁₋₆alkyl, —NHC(O)CH₃, halogen andtrifluoromethyl;

—W— is

B is selected from the group consisting of —C(═NR⁴⁶)(R⁴⁷), C(O)NR⁴⁰R⁴¹aryl, heteroaryl, heteroalicyclic, S(O)₂R⁸, C(O)R⁷, XR^(8a),(C₁₋₆)alkylNR⁴⁰R⁴¹, (C₁₋₆)alkylCOOR^(8b); wherein said aryl, heteroaryl,and heteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to three same or different substituentsselected from the group F; wherein aryl is napthyl or substitutedphenyl; wherein heteroaryl is a mono or bicyclic system which containsfrom 3 to 7 ring atoms for a mono cyclic system and up to 12 atoms in afused bicyclic system, including from 1 to 4 heteroatoms; whereinheteroalicyclic is a 3 to 7 membered mono cyclic ring which may containfrom 1 to 2 heteroatoms in the ring skeleton and which may be fused to abenzene or pyridine ring;q is 0, 1, or 2;D is selected from the group consisting of (C₁₋₆)alkyl and(C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl are optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from the group consistingof C(O)NR⁵⁵R⁵⁶, hydroxy, cyano and XR⁵⁷;E is selected from the group consisting of (C₁₋₆)alkyl and(C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl areindependently optionally substituted with a member selected from thegroup consisting of phenyl, heteroaryl, SMe, SPh, —C(O)NR₅₆R₅₇, C(O)R₅₇,SO₂(C₁₋₆)alkyl and SO₂Ph; wherein heteroaryl is a monocyclic systemwhich contains from 3 to 7 ring atoms, including from 1 to 4heteroatoms;F is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, (C₁₋₆)thioalkoxy, cyano, halogen, nitro,—C(O)R⁵⁷, benzyl, —NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl,—NR⁴²C(O)-aryl, —NR⁴²C(O)-heteroaryl, —NR⁴²C(O)-heteroalicyclic, a 4, 5,or 6 membered ring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)allkyl,—NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴²S(O)2-aryl, —NR⁴²S(O)₂-heteroaryl,—NR⁴²S(O)2-heteroalicyclic, S(O)₂(C₁₋₆)alkyl, S(O)₂aryl, —S(O)2NR⁴²R⁴³,NR⁴²R⁴³, (C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³, NHC(O)NR⁴²R⁴³,OC(O)NR⁴²R⁴³, NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and(C₁₋₆)alkylCOOR⁵⁴; wherein said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl,heteroaryl, heteroalicyclic, (C₁₋₆)alkoxy, and aryloxy, are optionallysubstituted with one to nine same or different halogens or from one tofive same or different substituents selected from the group G; whereinaryl is phenyl; heteroaryl is a monocyclic system which contains from 3to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;G is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, cyano, halogen, nitro, —C(O)R⁵⁷, benzyl,—NR⁴⁸C(O)—(C₁₋₆)allkyl, —NR⁴⁸C(O)—(C₃₋₆)cycloalkyl, —NR⁴⁸C(O)-aryl,—NR⁴⁸C(O)-heteroaryl, —NR⁴⁸C(O)-heteroalicyclic, a 4, 5, or 6 memberedring cyclic N-lactam, —NR⁴⁸S(O)₂—(C₁₋₆)alkyl,—NR⁴⁸S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴⁸S(O)2-aryl, —NR⁴⁸S(O)₂-heteroaryl,—NR⁴⁸S(O)2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR⁴⁸R⁴⁹,(C₁₋₆)allkyl C(O) NR⁴⁸R⁴⁹, C(O) NR⁴⁸R⁴⁹, NHC(O)NR⁴⁸R⁴⁹, OC(O) NR⁴⁸R⁴⁹,NHC(O)OR^(54′), (C₁₋₆)alkyl NR⁴⁸R⁴⁹, COOR⁵⁴, and (C₁₋₆)allkylCOOR⁵⁴;whereinaryl is phenyl; heteroaryl is a monocyclic system which contains from 3to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;R⁷ is selected from the group consisting of aryl, heteroaryl, andheteroalicyclic; wherein said aryl, heteroaryl, and heteroalicyclic areoptionally substituted with one to three same or different halogens orwith from one to three same or different substituents selected from thegroup F;wherein for R⁷, R⁸, R^(8a), R^(8b) aryl is phenyl; heteroaryl is a monoor bicyclic system which contains from 3 to 7 ring atoms for mono cyclicsystems and up to 10 atoms in a bicyclic system, including from 1 to 4heteroatoms; wherein heteroalicyclic is selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine;R⁸ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic; wherein said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic are optionally substituted withone to six same or different halogens or from one to five same ordifferent substituents selected from the group F;R^(8a) is a member selected from the group consisting of aryl,heteroaryl, and heteroalicyclic; wherein each member is independentlyoptionally substituted with one to six same or different halogens orfrom one to five same or different substituents selected from the groupF;R^(8b) is selected from the group consisting of hydrogen, (C₁₋₆)alkyland phenyl; R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ are each independentlyselected from the group consisting of hydrogen and (C₁₋₆)alkyl; whereinsaid (C₁₋₆)alkyl is optionally substituted with one to three same ordifferent halogens;X is selected from the group consisting of NH or NCH₃, 0, and S;R⁴⁰ and R⁴¹ are independently selected from the group consisting of(a) hydrogen; (b) (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl substituted with oneto three same or different halogens or from one to two same or differentsubstituents selected from the group F; and (c) (C₁₋₆)alkoxy, aryl,heteroaryl or heteroalicyclic; or R⁴⁰ and R⁴¹ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMepiperazine, piperidine, azepine, and morpholine; and wherein said aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or from one to two same or differentsubstituents selected from the group F; wherein for R⁴⁰ and R⁴¹ aryl isphenyl; heteroaryl is a monocyclic system which contains from 3 to 6ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine; provided when B is C(O)NR⁴⁰R⁴¹, at least one of R⁴⁰ and R⁴¹is not selected from groups (a) or (b);R⁴² and R⁴³ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, allyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl,heteroaryl and heteroalicyclic; or R⁴² and R⁴³ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMepiperazine, piperidine, azepine, and morpholine; and wherein said(C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl, heteroaryl, andheteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to two same or different substituentsselected from the group G; wherein for R⁴² and R⁴³ aryl is phenyl;heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms,including from 1 to 4 heteroatoms; heteroalicyclic is a member selectedfrom the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;R_(a) and R_(b) are each independently H, (C₁₋₆)alkyl or phenyl;R⁴⁶ is selected from the group consisting of H, OR⁵⁷, and NR⁵⁵R⁵⁶;R⁴⁷ is selected from the group consisting of H, amino, halogen, phenyl,and (C₁₋₆)alkyl;R⁴⁸ and R⁴⁹ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl and phenyl;R⁵⁰ is selected from the group consisting of H, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, and benzyl; wherein each of said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl and benzyl are optionally substituted with one to threesame or different halogen, amino, OH, CN or NO₂;R⁵⁴ is selected from the group consisting of hydrogen and (C₁₋₆)alkyl;R^(54′) is (C₁₋₆)alkyl;R⁵⁵ and R⁵⁶ are independently selected from the group consisting ofhydrogen and (C₁₋₆)alkyl; andR⁵⁷ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl andphenyl.

A preferred embodiment are compounds of Formula I, includingpharmaceutically acceptable salts thereof,

wherein:R¹ is hydrogen;Q is either:(a)

wherein R² is selected from the group consisting of hydrogen, halogen,hydroxy, —O(C₁₋₆)alkyl, cyano, nitro and XR⁵⁷;

wherein R³ is selected from the group consisting of hydrogen, halogen,hydroxy, —O(C₁₋₆)alkyl, cyano, —COOR⁵⁶, nitro, XR⁵⁷; phenyl optionallysubstituted with one to three same or different halogens or one ofmethoxy, hydroxy or XR⁵⁷; furyl, oxazolyl, or pyrazolyl, independentlyoptionally substituted with halogen, methoxy, (C₁₋₃)alkyl or XR⁵⁷; or

(b) Q is:

wherein R² and R³ are independently selected from the group consistingof hydrogen, halogen, hydroxy, —O(C₁₋₆)alkyl, cyano, nitro, —COOR⁵⁶,XR⁵⁷, —C(O) NR⁵⁵R⁵⁶; phenyl optionally substituted with one to threesame or different halogens or one of methoxy, hydroxy or XR⁵⁷; furyl,oxalzolyl or pyrazolyl, independently optionally substituted with(C₁₋₃)alkyl, halogen, methoxy or XR⁵⁷;and for both (a) and (b):m is 2;R⁵ is hydrogen;R⁶ does not exist;A is selected from the group consisting of C₁₋₆alkoxy, aryl andheteroaryl; wherein said aryl is phenyl; heteroaryl is selected from thegroup consisting of pyridinyl, pyrimidinyl, pyrazinyl, triazinyl,furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl andisoxazolyl; and said aryl or heteroaryl is optionally substituted withone or two of the same or different members selected from the groupconsisting of amino, cyano, hydroxy C₁₋₆alkoxy, C₁₋₆alkyl, —NHC(O)CH₃,halogen and trifluoromethyl;— represents a carbon-carbon bond;

X is NH or NCH₃;

R⁵⁷ is H or (C₁₋₃)alkyl; andR⁵⁵ and R⁵⁶ are independently H or (C₁₋₆)alkyl.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:A is selected from the group consisting of phenyl and heteroaryl;wherein heteroaryl is pyridinyl, furanyl or thienyl; and said phenyl orsaid heteroaryl is optionally substituted with one to two of the same ordifferent amino, C₁₋₆alkyl, hydroxy, or halogen;R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are each independently hydrogenor methyl with the proviso that only one is methyl;Q is either:(a)

and then R² is selected from the group consisting of hydrogen, halogenand methoxy; andR₃ is hydrogen; or

(b) Q is:

and R² is halogen or hydrogen and R³ is hydrogen;and for both (a) and (b):R⁴ is selected from the group consisting of B;B is selected from the group consisting of —C(O)NR⁴⁰R⁴¹, substitutedphenyl, heteroaryl, oxazoline, pyrazinone and methylene dioxy orethylene dioxy fused to a benzene or pyridine; wherein said heteroarylor phenyl is optionally substituted with one to three same or differenthalogens or from one to two same or different substituents selected fromthe group F.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is selected from the group consisting of —C(O)NR⁴⁰R⁴¹, substitutedphenyl and heteroaryl; wherein said phenyl is substituted and heteroarylis optionally substituted with one to three same or different halogensor from one to two same or different substituents selected from thegroup F;F is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, (C₁₋₆)thioalkoxy, cyano, halogen, —C(O)R⁵⁷, benzyl,—NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl, —NR⁴²C(O)-aryl,—NR⁴²C(O)-heteroaryl, —NR⁴²C(O)-heteroalicyclic, 4, 5, or 6 memberedring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)alkyl, —NR⁴²R⁴³, C(O)NR⁴²R⁴³ andCOOR⁵⁴;wherein said (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, aryl, heteroaryl,heteroalicyclic, (C₁₋₆)alkoxy, are optionally substituted with one tothree same or different halogens or from one to two same or differentsubstituents selected from the group G;G is selected from the group consisting of (C₁₋₆)alkyl, hydroxy,(C₁₋₆)alkoxy, halogen, —NR⁴⁸C(O)—(C₁₋₆)alkyl, —NR⁴⁸C(O)—(C₃)cycloalkyl,4, 5, or 6 membered ring cyclic N-lactam, —NR⁴⁸S(O)₂—(C₁₋₆)alkyl,NR⁴⁸R⁴⁹, (C₁₋₆)alkyl C(O)NR⁴⁸R⁴⁹, C(O)NR⁴⁸R⁴⁹ and (C₁₋₆)alkylNR⁴⁸R⁴⁹;R⁴⁰ is hydrogen; andR⁴¹ is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, phenyl and heteroaryl; wherein said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, phenyl, or heteroaryl are substituted with one tothree same or different halogens or one to two same or differentsubstituents selected from the group consisting of methyl, (C₁₋₃)alkoxy,heteroaryl and aryl; wherein said aryl or heteroaryl are optionallysubstituted with one to three same or different halogens or from one totwo same or different substituents selected from the group consisting of(C₁₋₆)alkyl, hydroxy, (C₁₋₆)alkoxy, —NR⁴²C(O)—(C₁₋₆)alkyl, NR⁴²R⁴³ andC(O)NR⁴²R⁴³.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:

Q is

A is Phenyl, 2-pyridyl, or 3-pyridyl;B is selected from the group consisting of —C(O)NR⁴⁰R⁴¹ or heteroaryl;wherein said heteroaryl is optionally substituted with one to three sameor different halogens or from one to two same or different substituentsselected from the group F.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is heteroaryl, wherein said heteroaryl is optionally substituted withone to three same or different halogens or from one to two same ordifferent substituents selected from the group F.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:

Q is

R² is selected from the group consisting of hydrogen, halogen, andmethoxy;

R⁴ is B;

B is selected from the group consisting of —C(O)NR⁴⁰R⁴¹ or heteroaryl;wherein said heteroaryl is optionally substituted with one to three sameor different halogens or from one to two same or different substituentsselected from the group F.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:A is phenyl, 2-pyridyl, or 3-pyridyl.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:

B is —C(O)NR⁴⁰R⁴¹.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is heteroaryl, wherein said heteroaryl is optionally substituted withone to three same or different halogens or from one to two same ordifferent substituents selected from the group F.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:F is selected from the group consisting of (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl(C₁₋₆)alkoxy, hydroxy, heteroaryl, heteroalicyclic, methoxy,—S(C₁₋₃)alkyl, halogen, —C(O)R⁵⁷, C(O)NR⁴²R⁴³, —NR⁴²C(O)—(C₁₋₆)alkyl,—NR⁴²C(O)—(C₃₋₆)cycloalkyl, —NR⁴²C(O)-aryl, —NR⁴²C(O)-heteroaryl,—NR⁴²C(O)-heteroalicyclic, 4, 5, or 6 membered ring cyclic N-lactam,—NR⁴²S(O)₂—(C₁₋₆)alkyl, —NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴²S(O)2-aryl,—NR⁴²S(O)₂-heteroaryl, —NR⁴²S(O)2-heteroalicyclic, NR⁴²R⁴³,NR⁵⁵(C₁₋₃)allkylNR⁵⁵R⁵⁶ and COOR⁵⁴.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:A is phenyl, 2-pyridyl, or 3-pyridyl.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof, wherein:

Q is

R² is selected from the group consisting of hydrogen and methoxy;R³ is hydrogen; andB is selected from the group consisting of —C(O)NR⁴⁰R⁴¹ and heteroaryl;wherein said heteroaryl is optionally substituted with one to three sameor different halogens or from one to two same or different substituentsselected from the group F.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:R² is fluoro.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:R² is methoxy.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is heteroaryl selected from the group consisting of thiazole,pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole,furyl, thienyl, oxazole, oxadiazole, thiadiazole, pyrimidine, pyrazole,triazine, triazole, tetrazole, pyridyl, indole, azaindole, anddiaza-indole; wherein said heteroaryl is optionally substituted with oneto three same or different halogens or from one to two same or differentsubstituents selected from the group F.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is heteroaryl selected from the group consisting of thiazole,pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole,furyl, thienyl, oxazole, oxadiazole, thiadiazole, pyrimidine, pyrazole,triazine, triazole, tetrazole, pyridyl, indole, azaindole, anddiaza-indole; wherein said heteroaryl is optionally substituted with oneto three same or different halogens or from one to two same or differentsubstituents selected from the group F.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is heteroaryl selected from the group consisting of thiazole,pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole,furyl, thienyl, oxazole, oxadiazole, thiadiazole, pyrimidine, pyrazole,triazine, triazole, tetrazole, pyridyl, indole, azaindole, anddiaza-indole; wherein said heteroaryl is optionally substituted with oneto three same or different halogens or from one to two same or differentsubstituents selected from the group F.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is heteroaryl selected from the group consisting of thiazole,pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole,furyl, thienyl, oxazole, oxadiazole, thiadiazole, pyrimidine, pyrazole,triazine, triazole, tetrazole, pyridyl, indole, azaindole, anddiaza-indole; wherein said heteroaryl is optionally substituted with oneto three same or different halogens or from one to two same or differentsubstituents selected from the group F.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is heteroaryl optionally substituted with one to three same ordifferent halogens or a substituent selected from the group consistingof hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₃ thioalkoxy, amino, —C(O)H,—COOH, —COOC₁-C₆ alkyl, —NHC(O)—(C₁-C₆ alkyl), —NHS(O)₂—(C₁-C₆ alkyl),—C(O)—NH₂, C(O)NHMe, C(O)NMe2, trifluoromethyl, —NR⁵⁵R⁵⁶, NR⁵⁵R⁵⁶—(C₁-C₆alkyl)-NR⁵⁵R⁵⁶, -thiazole, pyrrole, piperazine, pyrrolidine andN-pyrrolidone.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is —C(O)NH-heteroaryl wherein said heteroaryl is optionallysubstituted with one to three same or different halogens or asubstituent selected from the group consisting of (C₁-C₆ alkyl), amino,—NHC(O)—(C₁-C₆ alkyl), -methoxy, —NHC(C₁-C₆ alkyl) and —N(C₁-C₆ alkyl)₂.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is heteroaryl optionally substituted with one to three same ordifferent halogens or a substituent selected from the group consistingof (C₁-C₆ alkyl), amino, —NHC(O)—(C₁-C₆ alkyl), —NHS(O)₂—(C₁-C₆ alkyl),methoxy, —C(O)—NH₂, C(O)NHMe, C(O)NMe2, trifluoromethyl, —NHC(C₁-C₆alkyl), —N(C₁-C₆ alkyl)₂, -heteroaryl and a 4, 5, or 6 membered cyclicN-lactam.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is —C(O)NH-heteroaryl wherein said heteroaryl is optionallysubstituted with one to three same or different halogens or asubstituent selected from the group consisting of (C₁-C₆ alkyl), amino,—NHC(O)—(C₁-C₆ alkyl), -methoxy, —NHC(C₁-C₆ alkyl) and —N(C₁-C₆ alkyl)₂.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is heteroaryl optionally substituted with one to three same ordifferent halogens or a substituent selected from the group consistingof hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₃ thioalkoxy, amino, —C(O)H,—COOH, —COOC₁-C₆ alkyl, —NHC(O)—(C₁₋₆alkyl), —NHS(O)₂—(C₁-C₆ alkyl),methoxy, —C(O)—NH₂, C(O)NHMe, C(O)NMe2, trifluoromethyl, —NR⁵⁵R⁵⁶,NR⁵⁵R⁵⁶—(C₁-C₆ alkyl)-NR⁵⁵R⁵⁶, -thiazole, pyrrole, piperazine,pyrrolidine and N-pyrrolidone.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is —C(O)NH-heteroaryl wherein said heteroaryl is optionallysubstituted with one to three same or different halogens or asubstituent selected from the group consisting of (C₁-C₆ alkyl), amino,—NHC(O)—(C₁-C₆ alkyl), -methoxy, —NHC(C₁-C₆ alkyl) and —N(C₁-C₆ alkyl)₂.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is thienyl.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is thienyl optionally substituted with one to three same or differenthalogens or a substituent selected from the group consisting of hydroxy,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₃ thioalkoxy, amino, —C(O)H, —COOH,—COOC₁-C₆ alkyl, —NHC(O)—(C₁-C₆ alkyl), —NHS(O)₂—(C₁-C₆ alkyl),—C(O)—NH₂, C(O)NHMe, C(O)NMe2, trifluoromethyl, —NR⁵⁵R⁵⁶, NR⁵⁵R⁵⁶—(C₁-C₆alkyl)-NR⁵⁵R⁵⁶, heteroaryl, piperazine, pyrrolidine, N-pyrrolidone andtrifluoromethyl.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is thienyl.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is thienyl optionally substituted with one to three same or differenthalogens or a substituent selected from the group consisting of hydroxy,C₁-C₆ alkyl, amino, —NHC(O)—(C₁-C₆ alkyl), —C(O)—NH₂, C(O)NHMe, C(O)NMe₂and —NR⁵⁵R⁵⁶.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is thienyl optionally substituted with one to three same or differenthalogens or a substituent selected from the group consisting of hydroxy,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₃ thioalkoxy, amino, —C(O)H, —COOH,—COOC₁-C₆ alkyl, —NHC(O)—(C₁-C₆ alkyl), —NHS(O)₂—(C₁-C₆ alkyl), methoxy,—C(O)—NH₂, C(O)NHMe, C(O)NMe2, trifluoromethyl, —NR⁵⁵R⁵⁶, NR⁵⁵R⁵⁶—(C₁-C₆alkyl)-NR⁵⁵R⁵⁶, heteroaryl, piperazine, pyrrolidine, N-pyrrolidone andtrifluoromethyl.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is heteroaryl selected from the group consisting of thiazole,pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole,furyl, thienyl, oxazole, oxadiazole, thiadiazole, pyrimidine, pyrazole,triazine, triazole, tetrazole and pyridyl; wherein said heteroaryl isoptionally substituted with one to three same or different halogens or asubstituent selected from the group F consisting of hydroxy, C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₃ thioalkoxy, amino, —C(O)H, —COOH, —COOC₁-C₆alkyl, —NHC(O)—(C₁-C₆ alkyl), —NHS(O)₂—(C₁-C₆ alkyl), methoxy,—C(O)—NH₂, C(O)NHMe, C(O)NMe2, trifluoromethyl, —NR⁵⁵R⁵⁶, NR⁵⁵R⁵⁶—(C₁-C₆alkyl)-NR⁵⁵R⁵⁶, heteroaryl, piperazine, pyrrolidine, N-pyrrolidone andtrifluoromethyl.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is heteroaryl selected from the group consisting of thiazole,pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole,furyl, thienyl, oxazole, oxadiazole, thiadiazole, pyrimidine, pyrazole,triazine, triazole, tetrazole and pyridyl; wherein said heteroaryl isoptionally substituted with one to three same or different halogens or asubstituent selected from the group F consisting of hydroxy, C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₃ thioalkoxy, amino, —C(O)H, —COOH, —COOC₁-C₆alkyl, —NHC(O)—(C₁-C₆ alkyl), —NHS(O)₂—(C₁-C₆ alkyl), methoxy,—C(O)—NH₂, C(O)NHMe, C(O)NMe2, trifluoromethyl, —NR⁵⁵R⁵⁶, NR⁵⁵R⁵⁶—(C₁-C₆alkyl)-NR⁵⁵R⁵⁶, heteroaryl, piperazine, pyrrolidine, N-pyrrolidone andtrifluoromethyl.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is heteroaryl selected from the group consisting of thiazole,pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole,furyl, thienyl, oxazole, oxadiazole, thiadiazole, pyrimidine, pyrazole,triazine, triazole, tetrazole and pyridyl; wherein said heteroaryl isoptionally substituted with one to three same or different halogens or asubstituent selected from the group F consisting of hydroxy, C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₃ thioalkoxy, amino, —C(O)H, —COOH, —COOC₁-C₆alkyl, —NHC(O)—(C₁-C₆ alkyl), —NHS(O)₂—(C₁-C₆ alkyl), methoxy,—C(O)—NH₂, C(O)NHMe, C(O)NMe2, trifluoromethyl, —NR⁵⁵R⁵⁶, NR⁵⁵R⁵⁶—(C₁-C₆alkyl)-NR⁵⁵R⁵⁶, heteroaryl, piperazine, pyrrolidine, N-pyrrolidone andtrifluoromethyl.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:A compound of claim 3 is depicted in Table 2.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:A compound of claim 3 is depicted in Table 2-1.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:A compound of claim 3 is depicted in Table 3.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:A compound of claim 3 is depicted in Table 4.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:A compound of claim 3 is depicted in Table 5.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:A is selected from the group consisting of phenyl and heteroaryl;wherein heteroaryl is pyridinyl, furanyl or thienyl; wherein said phenylor heteroaryl is independently optionally substituted with one to two ofthe same or different amino, C₁₋₆alkyl, or halogen;— represents a carbon-carbon bond;R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ are each independentlyhydrogen or methyl, with the proviso that only zero, one, or two ismethyl;Q is either:(a)

R² is selected from the group consisting of hydrogen, halogen, andmethoxy; andR₃ is hydrogen; or

(b) Q is:

R² and R³ are hydrogen;and for both (a) and (b):R⁴ is selected from the group consisting of B;B is heteroaryl selected from the group consisting of triazole,pyrazole, oxazole, pyrazine, pyrimidine and oxadiazole; wherein saidheteroaryl is optionally substituted with one to three same or differenthalogens or from one to two same or different substituents selected fromthe group F;F is selected from the group consisting of (C₁₋₆)alkyl, heteroaryl,—NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²R⁴³ and C(O)NR⁴²R⁴³,R⁵ is hydrogen;R⁶ does not exist; andR⁴² and R⁴³ are independently selected from the group consisting ofhydrogen and (C₁₋₆)alkyl; or R⁴² and R⁴³ taken together with thenitrogen to which they are attached form a heteroalicyclic selected fromthe group consisting of aziridine, azetidine, pyrrolidine, piperazine,tetrahydrofuran, tetrahydropyran, azepine and morpholine.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:R² is H, Cl, F, or methoxy; andR⁴ is selected from the group consisting of

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:R² is methoxy or fluoro; andone of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, or R¹⁶ is methyl and the othersare hydrogen.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:R² is methoxy; andR⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, or R¹⁶ are each hydrogen.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:one of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, or R¹⁶ is (R)-methyl and theothers are hydrogen.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:one of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, or R¹⁶ is (S)-methyl and theothers are hydrogen.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:R² is methoxy, hydrogen, chloro, or fluoro; andR⁴ is oxadiazole.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:R² is methoxy, hydrogen, chloro or fluoro; andR⁴ is oxadiazole substituted with a single fluoro, chloro, amino ormethyl group.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:A is selected from the group consisting of phenyl and heteroaryl;wherein said heteroaryl is pyridinyl, furanyl or thienyl; and saidphenyl or said heteroaryl is optionally substituted with one to two ofthe same or different amino, C₁₋₆alkyl, hydroxy, or halogen;R⁹, R¹⁰, R¹¹, R¹², R¹⁵, or R¹⁶ are each hydrogen;R¹³ and R¹⁴ are each independently hydrogen or methyl with the provisothat only one is methyl;Q is either:(a)

R² is selected from the group consisting of hydrogen, halogen andmethoxy; andR₃ is hydrogen; or

(b) Q is:

and R² is halogen or hydrogen and R³ is hydrogen;and for both (a) and (b):R⁴ is selected from the group consisting of B; andB is selected from thegroup consisting of —C(O)NR⁴⁰R⁴¹, substitutedphenyl, heteroaryl, oxazoline, pyrazinone, methylene dioxy or ethylenedioxy fused to a benzene or pyridine; wherein said heteroaryl or phenylis optionally substituted with one to three same or different halogensor from one to two same or different substituents selected from thegroup F.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is selected from the group consisting of —C(O)NR⁴⁰R⁴¹, substitutedphenyl and heteroaryl; wherein said phenyl is substituted and heteroarylis optionally substituted with one to three same or different halogensor from one to two same or different substituents selected from thegroup F;

F is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, (C₁₋₆)thioalkoxy, cyano, halogen, —C(O)R⁵⁷, benzyl,—NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl, —NR⁴²C(O)-aryl,—NR⁴²C(O)-heteroaryl, —NR⁴²C(O)-heteroalicyclic, 4, 5, or 6 memberedring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)alkyl, —NR⁴²R⁴³, C(O)NR⁴²R⁴³ andCOOR⁵⁴, wherein said (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, aryl, heteroaryl,heteroalicyclic, (C₁₋₆)alkoxy, are optionally substituted with one tothree same or different halogens or from one to two same or differentsubstituents selected from the group G;

G is selected from the group consisting of (C₁₋₆)alkyl, hydroxy,(C₁₋₆)alkoxy, halogen, —NR⁴⁸C(O)—(C₁₋₆)alkyl, —NR⁴⁸C(O)—(C₃)cycloalkyl,4, 5, or 6 membered ring cyclic N-lactam, —NR⁴⁸S(O)₂—(C₁₋₆)alkyl,NR⁴⁸R⁴⁹, C(O)NR⁴⁸R⁴⁹, C(O)NR⁴⁸R⁴⁹ and (C₁₋₆)alkylNR⁴⁸R⁴⁹;R⁴⁰ is hydrogen;R⁴¹ is (C₃₋₇)cycloalkyl, phenyl, or heteroaryl; wherein said(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, phenyl, or heteroaryl are substitutedwith one to three same or different halogens or one to two same ordifferent methyl, (C₁₋₃)alkoxy, heteroaryl or aryl; wherein said aryl orheteroaryl are optionally substituted with one to three same ordifferent halogens or from one to two same or different substituentsselected from the group consisting of (C₁₋₆)alkyl, hydroxy, (C₁₋₆)alkoxy—NR⁴²C(O)—(C₁₋₆)alkyl, NR⁴²R⁴³ and C(O)NR⁴²R⁴³.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:A is selected from the group consisting of phenyl and heteroaryl;wherein heteroaryl is pyridinyl, furanyl or thienyl; and said phenyl orsaid heteroaryl is optionally substituted with one to two of the same ordifferent amino, C₁₋₆alkyl, hydroxy, or halogen;R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are each independently hydrogenor methyl with the proviso that only one is methyl;Q is either:(a)

wherein R² is selected from the group consisting of hydrogen, halogenand methoxy; andR₃ is hydrogen; or

(b) Q is:

wherein R² is halogen or hydrogen; and R³ is hydrogen;and for both (a) and (b):R⁴ is selected from the group consisting of B;B is selected from thegroup consisting of —C(O)NR⁴⁰R⁴¹, substitutedphenyl, heteroaryl, oxazoline, pyrazinone, methylene dioxy or ethylenedioxy fused to a benzene or pyridine; wherein said heteroaryl or phenylis optionally substituted with one to three same or different halogensor from one to two same or different substituents selected from thegroup F.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is selected from the group consisting of pyrazinone and methylenedioxy or ethylene dioxy fused to a benzene ring; wherein said group isoptionally substituted with one to three same or different halogens or asubstituent selected from the group F consisting of (C₁-C₆ alkyl),amino, —NHC(O)—(C₁-C₆ alkyl), —NHS(O)₂—(C₁-C₆ alkyl), methoxy,—C(O)—NH₂, C(O)NHMe, C(O)NMe2, trifluoromethyl, —NHC(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, -heteroaryl and a 4, 5, or 6 membered cyclic N-lactam.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:B is selected from the group consisting of oxadiazole, triazole,pyrazole, pyrazine and pyrimidine; wherein said group is optionallysubstituted with one to three same or different halogens or asubstituent selected from the group F consisting of (C₁-C₆ alkyl),amino, —NHC(O)—(C₁-C₆ alkyl), —NHS(O)₂—(C₁-C₆ alkyl), methoxy,—C(O)—NH₂, C(O)NHMe, C(O)NMe2, trifluoromethyl, —NHC(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, -heteroaryl, a 4, 5, or 6 membered cyclic N-lactam and(C₁₋₆)alkylNR⁴⁸R⁴⁹.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:heteroaryl in B is selected from the group consisting of pyrazine andpyrimidine.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:heteroaryl in B is selected from the group consisting of pyrazine andpyrimidine.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:wherein R⁹, R¹⁰, R¹⁵ and R¹⁶ are each hydrogen; and R¹¹, R¹², R¹³, andR¹⁴ are each independently hydrogen or methyl with the proviso that upto one can be methyl.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:one of R¹¹, R¹², R¹³, and R¹⁴ is methyl.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:the carbon atom of the piperazine ring to which the methyl group of R¹¹,R¹², R¹³, and R¹⁴ is attached has an (R) configuration.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:R¹¹, R¹², R¹³, and R¹⁴ are each hydrogen; and R⁹, R¹⁰, R¹⁵ and R¹⁶ areeach independently hydrogen or methyl with the proviso that up to onecan be methyl.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:one of R⁹, R¹⁰, R¹⁵ and R¹⁶ is methyl.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:the carbon atom of the piperazine ring to which the methyl group of R⁹,R¹⁰, R¹⁵ and R¹⁶ is attached has an (R) configuration.

Another preferred embodiment of the invention are compounds of FormulaI, including pharmaceutically acceptable salts thereof,

wherein:R¹ is hydrogen;m is 2;R⁵ is hydrogen;R⁶ does not exist;A is selected from the group consisting of C₁₋₆alkoxy, aryl andheteroaryl; wherein aryl is phenyl; heteroaryl is selected from thegroup consisting of pyridinyl, pyrimidinyl, pyrazinyl, triazinyl,furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl andisoxazolyl; and said aryl or heteroaryl is optionally substituted withone or two of the same or different amino, cyano, hydroxy C₁₋₆alkoxy,C₁₋₆alkyl, —NHC(O)CH₃, halogen and trifluoromethyl; and— represents a carbon-carbon bond.

A most preferred embodiment is a compound of Formula Ia, includingpharmaceutically acceptable salts thereof,

wherein:R² is methoxy, fluoro or chloro.R⁴ is selected from the group consisting of either:

which is a 1,2,3 triazole directly attached via the nitrogen atom ofposition 1 of the triazole wherein said 1,2,3 triazole is substitutedwith D at position 4 or R⁴ is:

which is a 1,2,4 triazole attached via the nitrogen atom of position 1of the triazole wherein said 1,2,4 triazole is substituted with E atposition 3.D is selected from hydrogen or C₁-C₃ alkyl.E is selected from the group consisting hydrogen, (C₁-C₃)alkyl,O(C₁-C₃)alkyl or CH₂OCH₃.R¹¹ is either hydrogen or methyl in which the configuration to which themethyl is attached is (R) with the proviso that when R⁴ is 1,2,3triazole, then R¹¹ is hydrogen.

Another embodiment of the invention is a pharmaceutical formulationcomprising an antiviral effective amount of a compound of Formula I,including pharmaceutically acceptable salts thereof and apharmaceutically acceptable carrier. When used for treating HIVinfection, said formulation can optionally additionally contain anantiviral effective amount of an AIDS treatment agent selected from thegroup consisting of: an AIDS antiviral agent; an antiinfective agent; animmunomodulator; and HIV entry inhibitors.

A third embodiment of the invention is a method for treating mammalsinfected with a virus, such as HIV, comprising administering to saidmammal an antiviral effective amount of a compound of Formula I,including pharmaceutically acceptable salts thereof, a pharmaceuticallyacceptable carrier, optionally in combination with an antiviraleffective amount of an AIDS treatment agent selected from the groupconsisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent;(c) an immunomodulator; and (d) HIV entry inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

Since the compounds of the present invention, may possess asymmetriccenters and therefore occur as mixtures of diastereomers andenantiomers, the present invention includes the individualdiastereoisomeric and enantiomeric forms of the compounds of Formula Iin addition to the mixtures thereof.

DEFINITIONS

The term “C₁₋₆ alkyl” as used herein and in the claims (unless specifiedotherwise) mean straight or branched chain alkyl groups such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and thelike.

“Halogen” refers to chlorine, bromine, iodine or fluorine.

An “aryl” group refers to an all carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, napthalenyl andanthracenyl. The aryl group may be substituted or unsubstituted. Whensubstituted the substituted group(s) is preferably one or more selectedfrom alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy,thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen,nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, aminoand —NR^(x)R^(y), wherein R^(x) and R^(y) are independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl, aryl,carbonyl, C-carboxy, sulfonyl, trihalomethyl, and, combined, a five- orsix-member heteroalicyclic ring.

As used herein, a “heteroaryl” group refers to a monocyclic or fusedring (i.e., rings which share an adjacent pair of atoms) group having inthe ring(s) one or more atoms selected from the group consisting ofnitrogen, oxygen and sulfur and, in addition, having a completelyconjugated pi-electron system. Unless otherwise indicated, theheteroaryl group may be attached at either a carbon or nitrogen atomwithin the heteroaryl group. It should be noted that the term heteroarylis intended to encompass an N-oxide of the parent heteroaryl if such anN-oxide is chemically feasible as is known in the art. Examples, withoutlimitation, of heteroaryl groups are furyl, thienyl, benzothienyl,thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl,quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzoxazolyl,benzimidazolyl, indolyl, isoindolyl, pyrazinyl. diazinyl, pyrazine,triazinyltriazine, tetrazinyl, and tetrazolyl. When substituted thesubstituted group(s) is preferably one or more selected from alkyl,cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido,amino, and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

As used herein, a “heteroalicyclic” group refers to a monocyclic orfused ring group having in the ring(s) one or more atoms selected fromthe group consisting of nitrogen, oxygen and sulfur. The rings may alsohave one or more double bonds. However, the rings do not have acompletely conjugated pi-electron system. Examples, without limitation,of heteroalicyclic groups are azetidinyl, piperidyl, piperazinyl,imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl,thiomorpholinyl and tetrahydropyranyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy,sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido,trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl,amino and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

An “alkyl” group refers to a saturated aliphatic hydrocarbon includingstraight chain and branched chain groups. Preferably, the alkyl grouphas 1 to 20 carbon atoms (whenever a numerical range; e.g., “1-20”, isstated herein, it means that the group, in this case the alkyl group maycontain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to andincluding 20 carbon atoms). More preferably, it is a medium size alkylhaving 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having1 to 4 carbon atoms. The alkyl group may be substituted orunsubstituted. When substituted, the substituent group(s) is preferablyone or more individually selected from trihaloalkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy,heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, andcombined, a five- or six-member heteroalicyclic ring.

A “cycloalkyl” group refers to an all-carbon monocyclic or fused ring(i.e., rings which share and adjacent pair of carbon atoms) groupwherein one or more rings does not have a completely conjugatedpi-electron system. Examples, without limitation, of cycloalkyl groupsare cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,cyclohexadiene, cycloheptane, cycloheptatriene and adamantane. Acycloalkyl group may be substituted or unsubstituted. When substituted,the substituent group(s) is preferably one or more individually selectedfrom alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroarylloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalo-methanesulfonamido, trihalomethanesulfonyl, silyl,guanyl, guanidino, ureido, phosphonyl, amino and —NR^(x)R^(y) with R^(x)and R^(y) as defined above.

An “alkenyl” group refers to an alkyl group, as defined herein,consisting of at least two carbon atoms and at least one carbon-carbondouble bond.

An “alkynyl” group refers to an alkyl group, as defined herein,consisting of at least two carbon atoms and at least one carbon-carbontriple bond.

A “hydroxy” group refers to an —OH group.

An “alkoxy” group refers to both an —O-alkyl and an —O-cycloalkyl groupas defined herein.

An “aryloxy” group refers to both an —O-aryl and an —O-heteroaryl group,as defined herein.

A “heteroaryloxy” group refers to a heteroaryl-O— group with heteroarylas defined herein.

A “heteroalicycloxy” group refers to a heteroalicyclic-O— group withheteroalicyclic as defined herein.

A “thiohydroxy” group refers to an —SH group.

A “thioalkoxy” group refers to both an S-alkyl and an —S-cycloalkylgroup, as defined herein.

A “thioaryloxy” group refers to both an —S-aryl and an —S-heteroarylgroup, as defined herein.

A “thioheteroaryloxy” group refers to a heteroaryl-S— group withheteroaryl as defined herein.

A “thioheteroalicycloxy” group refers to a heteroalicyclic-S— group withheteroalicyclic as defined herein.

A “carbonyl” group refers to a —C(═O)—R″ group, where R″ is selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon), as each is definedherein.

An “aldehyde” group refers to a carbonyl group where R″ is hydrogen.

A “thiocarbonyl” group refers to a —C(═S)—R″ group, with R″ as definedherein.

A “Keto” group refers to a —CC(═O)C— group wherein the carbon on eitheror both sides of the C═O may be alkyl, cycloalkyl, aryl or a carbon of aheteroaryl or heteroaliacyclic group.

A “trihalomethanecarbonyl” group refers to a Z₃CC(═O)— group with said Zbeing a halogen.

A “C-carboxy” group refers to a —C(═O)O—R″ groups, with R″ as definedherein.

An “O-carboxy” group refers to a R″C(—O)O— group, with R″ as definedherein.

A “carboxylic acid” group refers to a C-carboxy group in which R″ ishydrogen.

A “trihalomethyl” group refers to a —CZ₃, group wherein Z is a halogengroup as defined herein.

A “trihalomethanesulfonyl” group refers to an Z₃CS(═O)₂— groups with Zas defined above.

A “trihalomethanesulfonamido” group refers to a Z₃CS(═O)₂NR^(x)— groupwith Z and R^(X) as defined herein.

A “sulfinyl” group refers to a —S(═O)—R″ group, with R″ as definedherein and, in addition, as a bond only; i.e., —S(O)—.

A “sulfonyl” group refers to a —S(═O)₂R″ group with R″ as defined hereinand, in addition as a bond only; i.e., —S(O)₂—.

A “S-sulfonamido” group refers to a —S(═O)₂NR^(x)R^(y), with R^(x) andR^(y) as defined herein.

A “N-Sulfonamido” group refers to a R″S(═O)₂NR_(x)— group with R_(x) asdefined herein.

A “O-carbamyl” group refers to a —OC(═O)NR^(x)R^(y) as defined herein.

A “N-carbamyl” group refers to a WOC(═O)NR^(y) group, with R^(x) andR^(y) as defined herein.

A “O-thiocarbamyl” group refers to a —OC(═S)NR^(x)R^(y) group with R^(x)and R^(y) as defined herein.

A “N-thiocarbamyl” group refers to a —OC(═S)NR^(x)R^(y) group with R^(x)and R^(y) as defined herein.

An “amino” group refers to an —NH₂ group.

A “C-amido” group refers to a —C(═O)NR^(x)R^(y) group with R^(x) andR^(y) as defined herein.

A “C-thioamido” group refers to a —C(═S)NR^(x)R^(y) group, with R^(x)and R^(y) as defined herein.

A “N-amido” group refers to a R^(x)C(═O)NR^(y)— group, with R^(x) andR^(y) as defined herein.

A cyclic 4, 5, or six membered ring N-lactam refers to rings of 4, 5 or6 atoms containing a single amide group as two of the ring atoms whichis linked to the parent molecule at the amide nitrogen.

An “ureido” group refers to a —NR^(x)C(═O)NR^(y)R^(y2) group with R^(x)and R^(y) as defined herein and R^(y2) defined the same as R^(x) andR^(y).

A “guanidino” group refers to a —R^(x)NC(═N)NR^(y)R^(y2) group, withR^(x), R^(y) and R^(y2) as defined herein.

A “guanyl” group refers to a R^(x)R^(y)NC(═N)— group, with R^(x) andR^(y) as defined herein.

A “cyano” group refers to a —CN group.

A “silyl” group refers to a —Si(R″)₃, with R″ as defined herein.

A “phosphonyl” group refers to a P(═O)(OR^(x))₂ with R^(x) as definedherein.

A “hydrazino” group refers to a —NR^(x)NR^(y)R^(y2) group with R^(x),R^(y) and R^(y2) as defined herein.

Any two adjacent R groups may combine to form an additional aryl,cycloalkyl, heteroaryl or heterocyclic ring fused to the ring initiallybearing those R groups.

It is known in the art that nitrogen atoms in heteroaryl systems can be“participating in a heteroaryl ring double bond”, and this refers to theform of double bonds in the two tautomeric structures which comprisefive-member ring heteroaryl groups. This dictates whether nitrogens canbe substituted as well understood by chemists in the art. The disclosureand claims of the present invention are based on the known generalprinciples of chemical bonding. It is understood that the claims do notencompass structures known to be unstable or not able to exist based onthe literature.

Physiologically acceptable salts and prodrugs of compounds disclosedherein are within the scope of this invention. The term“pharmaceutically acceptable salt” as used herein and in the claims isintended to include nontoxic base addition salts. Suitable salts includethose derived from organic and inorganic acids such as, withoutlimitation, hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lacticacid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbicacid, aconitic acid, salicylic acid, phthalic acid, and the like. Theterm “pharmaceutically acceptable salt” as used herein is also intendedto include salts of acidic groups, such as a carboxylate, with suchcounterions as ammonium, alkali metal salts, particularly sodium orpotassium, alkaline earth metal salts, particularly calcium ormagnesium, and salts with suitable organic bases such as loweralkylamines (methylamine, ethylamine, cyclohexylamine, and the like) orwith substituted lower alkylamines (e.g. hydroxyl-substitutedalkylamines such as diethanolamine, triethanolamine ortris(hydroxymethyl)-aminomethane), or with bases such as piperidine ormorpholine.

In the method of the present invention, the term “antiviral effectiveamount” means the total amount of each active component of the methodthat is sufficient to show a meaningful patient benefit, i.e., healingof acute conditions characterized by inhibition of the HIV infection.When applied to an individual active ingredient, administered alone, theterm refers to that ingredient alone. When applied to a combination, theterm refers to combined amounts of the active ingredients that result inthe therapeutic effect, whether administered in combination, serially orsimultaneously. The terms “treat, treating, treatment” as used hereinand in the claims means preventing or ameliorating diseases associatedwith HIV infection.

The present invention is also directed to combinations of the compoundswith one or more agents useful in the treatment of AIDS. For example,the compounds of this invention may be effectively administered, whetherat periods of pre-exposure and/or post-exposure, in combination witheffective amounts of the AIDS antivirals, immunomodulators,antiinfectives, or vaccines, such as those in the following table.

Antivirals

Drug Name Manufacturer Indication 097 Hoechst/Bayer HIV infection, AIDS,ARC (non-nucleoside reverse transcriptase (RT) inhibitor) AmprenivirGlaxo Wellcome HIV infection, AIDS, 141 W94 ARC (protease GW 141inhibitor) Abacavir (1592U89) Glaxo Wellcome HIV infection, AIDS, GW1592 ARC (RT inhibitor) Acemannan Carrington Labs ARC (Irving, TX)Acyclovir Burroughs HIV infection, AIDS, Wellcome ARC, in combinationwith AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 TanoxBiosystems HIV infection, AIDS, ARC Adefovir dipivoxil Gilead SciencesHIV infection AL-721 Ethigen ARC, PGL (Los Angeles, CA) HIV positive,AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV incombination w/Retrovir Ansamycin Adria Laboratories ARC LM 427 (Dublin,OH) Erbamont (Stamford, CT) Antibody which Advanced AIDS, ARCNeutralizes pH Biotherapy Labile alpha aberrant Concepts Interferon(Rockville, MD) AR177 Aronex Pharm HIV infection, AIDS, ARCBeta-fluoro-ddA Nat'l Cancer AIDS-associated Institute diseasesBMS-232623 Bristol-Myers HIV infection, AIDS, (CGP-73547)Squibb/Novartis ARC (protease inhibitor) BMS-234475 Bristol-Myers HIVinfection, AIDS, (CGP-61755) Squibb/Novartis ARC (protease inhibitor)CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMVretinitis, herpes, papillomavirus Curdlan sulfate AJI Pharma USA HIVinfection Cytomegalovirus MedImmune CMV retinitis Immune globin CytoveneSyntex Sight threatening Ganciclovir CMV peripheral CMV retinitisDelaviridine Pharmacia-Upjohn HIV infection, AIDS, ARC (RT inhibitor)Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV Ind. Ltd. (Osaka,positive asymptomatic Japan) ddC Hoffman-La Roche HIV infection, AIDS,Dideoxycytidine ARC ddI Bristol-Myers HIV infection, AIDS,Dideoxyinosine Squibb ARC; combination with AZT/d4T DMP-450 AVID HIVinfection, AIDS, (Camden, NJ) ARC (protease inhibitor) Efavirenz DuPontMerck HIV infection, AIDS, (DMP 266) ARC (non-nucleoside(-)6-Chloro-4-(S)- RT inhibitor) cyclopropylethynyl- 4(S)-trifluoro-methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one, STOCRINE EL10 Elan Corp,PLC HIV infection (Gainesville, GA) Famciclovir Smith Kline herpeszoster, herpes simplex FTC Emory University HIV infection, AIDS, ARC(reverse transcriptase inhibitor) GS 840 Gilead HIV infection, AIDS, ARC(reverse transcriptase inhibitor) HBY097 Hoechst Marion HIV infection,AIDS, Roussel ARC (non-nucleoside reverse transcriptase inhibitor)Hypericin VIMRx Pharm. HIV infection, AIDS, ARC Recombinant Human TritonBiosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARCInterferon alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIVinfection, AIDS, ARC, asymptomatic HIV positive, also in combinationwith AZT/ddI/ddC ISIS 2922 ISIS CMV retinitis Pharmaceuticals KNI-272Nat'l Cancer HIV-assoc. diseases Institute Lamivudine, 3TC GlaxoWellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor);also with AZT Lobucavir Bristol-Myers CMV infection Squibb NelfinavirAgouron HIV infection, AIDS, Pharmaceuticals ARC (protease inhibitor)Nevirapine Boeheringer HIV infection, AIDS, Ingleheim ARC (RT inhibitor)Novapren Novaferon Labs, HIV inhibitor Inc. (Akron, OH) Peptide TPeninsula Labs AIDS Octapeptide (Belmont, CA) Sequence Trisodium AstraPharm. CMV retinitis, HIV Phosphonoformate Products, Inc. infection,other CMV infections PNU-140690 Pharmacia Upjohn HIV infection, AIDS,ARC (protease inhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4Sheffield Med. HIV infection, AIDS, Tech (Houston, TX) ARC RitonavirAbbott HIV infection, AIDS, ARC (protease inhibitor) SaquinavirHoffmann- HIV infection, AIDS, LaRoche ARC (protease inhibitor)Stavudine; d4T Bristol-Myers HIV infection, AIDS, Didehydrodeoxy- SquibbARC thymidine Valaciclovir Glaxo Wellcome Genital HSV & CMV infectionsVirazole Viratek/ICN asymptomatic HIV Ribavirin (Costa Mesa, CA)positive, LAS, ARC VX-478 Vertex HIV infection, AIDS, ARC ZalcitabineHoffmann-LaRoche HIV infection, AIDS, ARC, with AZT Zidovudine; AZTGlaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, incombination with other therapies Tenofovir disoproxil, Gilead HIVinfection, AIDS, fumarate salt (reverse transcriptase (VIREAD ®)inhibitor) COMBIVIR ® GSK HIV infection, AIDS, (reverse transcriptaseinhibitor) abacavir succinate GSK HIV infection, AIDS, (or ZIAGEN ®)(reverse transcriptase inhibitor) REYATAZ ® Bristol-Myers HIV infection(or atazanavir) Squibb AIDs, protease inhibitor FUZEON Roche/TrimerisHIV infection (or T-20) AIDs, viral Fusion inhibitor

Immunomodulators

Drug Name Manufacturer Indication AS-101 Wyeth-Ayerst AIDS BropiriminePharmacia Upjohn Advanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC(Irving, TX) CL246,738 American Cyanamid AIDS, Kaposi's Lederle Labssarcoma EL 10 Elan Corp, PLC HIV infection (Gainesville, GA) FP-21399Fuki ImmunoPharm Blocks HIV fusion with CD4+ cells Gamma InterferonGenentech ARC, in combination w/TNF (tumor necrosis factor) GranulocyteGenetics Institute AIDS Macrophage Colony Sandoz Stimulating FactorGranulocyte Hoechst-Roussel AIDS Macrophage Colony Immunex StimulatingFactor Granulocyte Schering-Plough AIDS, Macrophage Colony combinationStimulating Factor w/AZT HIV Core Particle Rorer Seropositive HIVImmunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT IL-2Hoffman-LaRoche AIDS, ARC, HIV, in Interleukin-2 Immunex combinationw/AZT IL-2 Chiron AIDS, increase in Interleukin-2 CD4 cell counts(aldeslukin) Immune Globulin Cutter Biological Pediatric AIDS, inIntravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS,Kaposi's (New Orleans, LA) sarcoma, ARC, PGL IMREG-2 Imreg AIDS,Kaposi's (New Orleans, LA) sarcoma, ARC, PGL Imuthiol Diethyl MerieuxInstitute AIDS, ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi'ssarcoma Interferon w/AZT, AIDS Methionine-Enkephalin TNI PharmaceuticalAIDS, ARC (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcomaMuramyl-Tripeptide Amgen AIDS, in combination Granulocyte w/AZT ColonyStimulating Factor Remune Immune Response Immunotherapeutic Corp. rCD4Genentech AIDS, ARC Recombinant Soluble Human CD4 rCD4-IgG AIDS, ARChybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 InterferonHoffman-La Roche Kaposi's sarcoma Alfa 2a AIDS, ARC, in combinationw/AZT SK&F106528 Smith Kline HIV infection Soluble T4 ThymopentinImmunobiology HIV infection Research Institute (Annandale, NJ) TumorNecrosis Genentech ARC, in combination Factor; TNF w/gamma Interferon

Anti-Infectives

Drug Name Manufacturer Indication Clindamycin with Pharmacia Upjohn PCPPrimaquine Fluconazole Pfizer Cryptococcal meningitis, candidiasisPastille Squibb Corp. Prevention of Nystatin Pastille oral candidiasisOrnidyl Merrell Dow PCP Eflornithine Pentamidine LyphoMed PCP treatmentIsethionate (IM & IV) (Rosemont, IL) Trimethoprim AntibacterialTrimethoprim/sulfa Antibacterial Piritrexim Burroughs Wellcome PCPtreatment Pentamidine Fisons Corporation PCP prophylaxis Isethionate forInhalation Spiramycin Rhone-Poulenc Cryptosporidial diarrheaIntraconazole- Janssen-Pharm. Histoplasmosis; R51211 cryptococcalmeningitis Trimetrexate Warner-Lambert PCP Daunorubicin NeXstar, SequusKaposi's sarcoma Recombinant Human Ortho Pharm. Corp. Severe anemiaErythropoietin assoc. with AZT therapy Recombinant Human SeronoAIDS-related Growth Hormone wasting, cachexia Megestrol AcetateBristol-Myers Squibb Treatment of anorexia assoc. W/AIDS TestosteroneAlza, Smith Kline AIDS-related wasting Total Enteral Norwich EatonDiarrhea and Nutrition Pharmaceuticals malabsorption related to AIDS

Additionally, the compounds of the invention herein may be used incombination with another class of agents for treating AIDS which arecalled HIV entry inhibitors. Examples of such HIV entry inhibitors arediscussed in DRUGS OF THE FUTURE 1999, 24(12), pp. 1355-1362; CELL, Vol.9, pp. 243-246, Oct. 29, 1999; and DRUG DISCOVERY TODAY, Vol. 5, No. 5,May 2000, pp. 183-194.

It will be understood that the scope of combinations of the compounds ofthis invention with AIDS antivirals, immunomodulators, anti-infectives,HIV entry inhibitors or vaccines is not limited to the list in the aboveTable, but includes in principle any combination with any pharmaceuticalcomposition useful for the treatment of AIDS.

Preferred combinations are simultaneous or alternating treatments ofwith a compound of the present invention and an inhibitor of HIVprotease and/or a non-nucleoside inhibitor of HIV reverse transcriptase.An optional fourth component in the combination is a nucleosideinhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. Apreferred inhibitor of HIV protease is indinavir, which is the sulfatesalt ofN-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)—N-(t-butylcarboxamido)-piperazinyl))-pentaneamideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred protease inhibitors are nelfinavir and ritonavir.Another preferred inhibitor of HIV protease is saquinavir which isadministered in a dosage of 600 or 1200 mg tid. Preferred non-nucleosideinhibitors of HIV reverse transcriptase include efavirenz. Thepreparation of ddC, ddI and AZT are also described in EPO 0,484,071.These combinations may have unexpected effects on limiting the spreadand degree of infection of HIV. Preferred combinations include thosewith the following (1) indinavir with efavirenz, and, optionally, AZTand/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/orddI and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3)stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and141W94 and 1592U89; (5) zidovudine and lamivudine.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

The preparative procedures and anti-HIV-1 activity of the novelazaindole piperazine diamide analogs of Formula I are summarized belowin Schemes 1-64.

ABBREVIATIONS

The following abbreviations, most of which are conventionalabbreviations well known to those skilled in the art, are usedthroughout the description of the invention and the examples. Some ofthe abbreviations used are as follows:

-   -   h=hour(s)    -   rt=room temperature    -   mol=mole(s)    -   mmol=millimole(s)    -   g=gram(s)    -   mg=milligram(s)    -   mL=milliliter(s)    -   TFA=Trifluoroacetic Acid    -   DCE=1,2-Dichloroethane    -   CH₂Cl₂=Dichloromethane    -   TPAP=tetrapropylammonium perruthenate    -   THF=Tetrahydofuran    -   DEPBT=3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one    -   DMAP=4-dimethylaminopyridine    -   P-EDC=Polymer supported        1-(3-dimethylaminopropyl)-3-ethylcarbodiimide    -   EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide    -   DMF=N,N-dimethylformamide    -   Hunig's Base=N,N-Diisopropylethylamine    -   mCPBA=meta-Chloroperbenzoic Acid    -   azaindole=1H-Pyrrolo-pyridine    -   4-azaindole=1H-pyrrolo[3,2-b]pyridine    -   5-azaindole=1H-Pyrrolo[3,2-c]pyridine    -   6-azaindole=1H-pyrrolo[2,3-c]pyridine    -   7-azaindole=1H-Pyrrolo[2,3-b]pyridine    -   PMB=4-Methoxybenzyl    -   DDQ=2,3-Dichloro-5,6-dicyano-1,4-benzoquinone    -   OTf=Trifluoromethanesulfonoxy    -   NMM=4-Methylmorpholine    -   PIP-COPh=1-Benzoylpiperazine    -   NaHMDS=Sodium hexamethyldisilazide    -   EDAC=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide    -   TMS=Trimethylsilyl    -   DCM=Dichloromethane    -   DCE=Dichloroethane    -   MeOH=Methanol    -   THF=Tetrahrdrofuran    -   EtOAc=Ethyl Acetate    -   LDA=Lithium diisopropylamide    -   TMP-Li=2,2,6,6-tetramethylpiperidinyl lithium    -   DME=Dimethoxyethane    -   DIBALH=Diisobutylaluminum hydride    -   HOBT=1-hydroxybenzotriazole    -   CBZ=Benzyloxycarbonyl    -   PCC=Pyridinium chlorochromate    -   Me=Methyl    -   Ph=Phenyl

Chemistry

The present invention comprises compounds of Formula I, theirpharmaceutical formulations, and their use in patients suffering from orsusceptible to HIV infection. The compounds of Formula I includepharmaceutically acceptable salts thereof.

General procedures to construct substituted azaindole piperazinediamides of Formula I and intermediates useful for their synthesis aredescribed in the following Schemes, 1-81.

Step A in Scheme 1 depicts the synthesis of an aza indole intermediate,2a, via the well known Bartoli reaction in which vinyl magnesium bromidereacts with an aryl or heteroaryl nitro group, such as in 1, to form afive-membered nitrogen containing ring as shown. Some references for theabove transformation include: Bartoli et al. a) Tetrahedron Lett. 1989,30, 2129. b) J. Chem. Soc. Perkin Trans. 1 1991, 2757. c) J. Chem. Soc.Perkin Trans. II 1991, 657. d) SynLett (1999), 1594. In the preferredprocedure, a solution of vinyl Magnesium bromide in THF (typically 1.0Mbut from 0.25 to 3.0M) is added dropwise to a solution of the nitropyridine in THF at -78° under an inert atmosphere of either nitrogen orArgon. After addition is completed, the reaction temperature is allowedto warm to −20° and then is stirred for approximately 12 h beforequenching with 20% aq ammonium chloride solution. The reaction isextracted with ethyl acetate and then worked up in a typical mannerusing a drying agent such as anhydrous magnesium sulfate or sodiumsulfate. Products are generally purified using chromatography overSilica gel. Best results are generally achieved using freshly preparedvinyl Magnesium bromide. In some cases, vinyl Magnesium chloride may besubstituted for vinyl Magnesium bromide.

Substituted azaindoles may be prepared by methods described in theliterature or may be available from commercial sources. Thus there aremany methods for carrying out step A in the literature and the specificexamples are too numerous to even list. Alternative syntheses of azaindoles and general methods for carrying out step A include, but are notlimited to, those described in the following references (a-k below): a)Prokopov, A. A.; Yakhontov, L. N. Khim.-Farm. Zh. 1994, 28(7), 30-51; b)Lablache-Combier, A. Heteroaromatics. Photoinduced Electron Transfer1988, Pt. C, 134-312; c) Saify, Zafar Said. Pak. J Pharmacol. 1986,2(2), 43-6; d) Bisagni, E. Jerusalem Symp. Quantum Chem. Biochem. 1972,4, 439-45; e) Yakhontov, L. N. Usp. Khim. 1968, 37(7), 1258-87; f)Willette, R. E. Advan. Heterocycl. Chem. 1968, 9, 27-105; g) Mahadevan,I.; Rasmussen, M. Tetrahedron 1993, 49(33), 7337-52; h) Mahadevan, I.;Rasmussen, M. J. Heterocycl. Chem. 1992, 29(2), 359-67; i) Spivey, A.C.; Fekner, T.; Spey, S. E.; Adams, H. J. Org. Chem. 1999, 64(26),9430-9443; j) Spivey, A. C.; Fekner, T.; Adams, H. Tetrahedron Lett.1998, 39(48), 8919-8922; k) Advances in Heterocyclic Chemistry (Academicpress) 1991, Vol. 52, pg 235-236 and references therein.

Step B. Intermediate 3a can be prepared by reaction of aza-indole,intermediate 2a, with an excess of ClCOCOOMe in the presence of AlCl₃(aluminum chloride) (Sycheva et al, Ref 26, Sycheva, T. V.; Rubtsov, N.M.; Sheinker, Yu. N.; Yakhontov, L. N. Some reactions of5-cyano-6-chloro-7-azaindoles and lactam-lactim tautomerism in5-cyano-6-hydroxy-7-azaindolines. Khim. Geterotsikl. Soedin., 1987,100-106). Typically an inert solvent such as CH₂Cl₂ is used but otherssuch as THF, Et₂O, DCE, dioxane, benzene, or toluene may findapplicability either alone or in mixtures. Other oxalate esters such asethyl or benzyl mono esters of oxalic acid could also suffice for eithermethod shown above. More lipophilic esters ease isolation during aqueousextractions. Phenolic or substituted phenolic (such aspentafluorophenol) esters enable direct coupling of the HW(C═O)A group,such as a piperazine, in Step D without activation. Lewis acidcatalysts, such as tin tetrachloride, titanium IV chloride, and aluminumchloride are employed in Step B with aluminum chloride being mostpreferred. Alternatively, the azaindole is treated with a Grignardreagent such as MeMgI (methyl magnesium iodide), methyl magnesiumbromide or ethyl magnesium bromide and a zinc halide, such as ZnCl₂(zinc chloride) or zinc bromide, followed by the addition of an oxalylchloride mono ester, such as ClCOCOOMe (methyl chlorooxoacetate) oranother ester as above, to afford the aza-indole glyoxyl ester (Shadrinaet al, Ref 25). Oxalic acid esters such as methyl oxalate, ethyl oxalateor as above are used. Aprotic solvents such as CH₂Cl₂, Et₂O, benzene,toluene, DCE, or the like may be used alone or in combination for thissequence. In addition to the oxalyl chloride mono esters, oxalylchloride itself may be reacted with the azaindole and then furtherreacted with an appropriate amine, such as a piperazine derivative (SeeScheme 52, for example).

Step C. Hydrolysis of the methyl ester, (intermediate 3a, Scheme 1)affords a potassium salt of intermediate 4a, which is coupled withmono-benzoylated piperazine derivatives as shown in Step D of Scheme 1.Some typical conditions employ methanolic or ethanolic sodium hydroxidefollowed by careful acidification with aqueous hydrochloric acid ofvarying molarity but 1M HCl is preferred. The acidification is notutilized in many cases as described above for the preferred conditions.Lithium hydroxide or potassium hydroxide could also be employed andvarying amounts of water could be added to the alcohols. Propanols orbutanols could also be used as solvents. Elevated temperatures up to theboiling points of the solvents may be utilized if ambient temperaturesdo not suffice. Alternatively, the hydrolysis may be carried out in anon polar solvent such as CH₂Cl₂ or THF in the presence of Triton B.Temperatures of −78° C. to the boiling point of the solvent may beemployed but −10° C. is preferred. Other conditions for ester hydrolysisare listed in reference 41 and both this reference and many of theconditions for ester hydrolysis are well known to chemists of averageskill in the art.

Alternative Procedures for Step B and C: Imidazolium Chloroaluminate:

We found that ionic liquid 1-alkyl-3-alkylimidazolium chloroaluminate isgenerally useful in promoting the Friedel-Crafts type acylation ofindoles and azaindoles. The ionic liquid is generated by mixing1-alkyl-3-alkylimidazolium chloride with aluminium chloride at roomtemperature with vigorous stirring. 1:2 or 1:3 molar ratio of1-alkyl-3-alkylimidazolium chloride to aluminium chloride is preferred.One particular useful imidazolium chloroaluminate for the acylation ofazaindole with methyl or ethyl chlorooxoacetate is the1-ethyl-3-methylimidazolium chloroaluminate. The reaction is typicallyperformed at ambient temperature and the azaindoleglyoxyl ester can beisolated. More conveniently, we found that the glyoxyl ester can behydrolyzed in situ at ambient temperature on prolonged reaction time(typically overnight) to give the corresponding glyoxyl acid for amideformation (Scheme 1).

A representative experimental procedure is as follows:1-ethyl-3-methylimidazolium chloride (2 equiv.; purchased from TCI;weighted under a stream of nitrogen) was stirred in an oven-dried roundbottom flask at r.t. under a nitrogen atmosphere, and added aluminiumchloride (6 equiv.; anhydrous powder packaged under argon in ampulespurchased from Aldrich preferred; weighted under a stream of nitrogen).The mixture was vigorously stirred to form a liquid, which was thenadded azaindole (1 equiv.) and stirred until a homogenous mixtureresulted. The reaction mixture was added dropwise ethyl or methylchlorooxoacetate (2 equiv.) and then stirred at r.t. for 16 h. Afterwhich time, the mixture was cooled in an ice-water bath and the reactionquenched by carefully adding excess water. The precipitates werefiltered, washed with water and dried under high vacuum to give theazaindoleglyoxyl acid. For some examples, 3 equivalents of1-ethyl-3-methylimidazolium chloride and chlorooxoacetate may berequired.

Related references: (1) Welton, T. Chem Rev. 1999, 99, 2071; (2)Surette, J. K. D.; Green, L.; Singer, R. D. Chem. Commun. 1996, 2753;(3) Saleh, R. Y. WO 0015594.

Step D. The acid intermediate, 4a, from step C of Scheme 1 is coupledwith an amine A(C═O)WH preferably in the presence of DEPBT(3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) andN,N-diisopropylethylamine, commonly known as Hunig's base, to provideazaindole piperazine diamides. DEPBT was prepared according to theprocedure of Ref. 28, Li, H.; Jiang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.;Goodman, M. Organic Lett., 1999, 1, 91-93. Typically an inert solventsuch as DMF or THF is used but other aprotic solvents could be used. Thegroup W as referred to herein is

The amide bond construction reaction could be carried out using thepreferred conditions described above, the EDC conditions describedbelow, other coupling conditions described in this application, oralternatively by applying the conditions or coupling reagents for amidebond construction described later in this application for constructionof substituents R₁-R₄. Some specific nonlimiting examples are given inthis application.

The mono-substituted piperazine derivatives can be prepared according towell established procedures such as those described by Desai et al, Ref27(a), Adamczyk et al, Ref 27(b), Rossen et al, Ref 27(c), and Wang etal, 27(d).

Additional procedures for synthesizing, modifying and attaching groups:(C═O)_(m)—WC(O)-A are contained in PCT WO 00/71535.

Scheme 2 provides a more specific example of the transformationspreviously described in Scheme 1. Intermediates 6-10 are prepared by themethodologies as described for intermediates 1a-5a in Scheme 1. Scheme2A is another embodiment of the transformations described in Schemes 1and 2. Conversion of the phenol to the chloride (Step S, Scheme 2A) maybe accomplished according to the procedures described in Reimann, E.;Wichmann, P.; Hoefner, G.; Sci. Pharm. 1996, 64(3), 637-646; andKatritzky, A. R.; Rachwal, S.; Smith, T. P.; Steel, P. J.; J.Heterocycl. Chem. 1995, 32(3), 979-984. Step T of Scheme 2A can becarried out as described for Step A of Scheme 1. The bromo intermediatecan then be converted into alkoxy, chloro, or fluoro intermediates asshown in Step U of Scheme 2A. Scheme 2A describes the preferred methodfor preparing intermediate 6c or other closely related compoundscontaining a 4 methoxy group in the 6-azaindole system. When step U isthe conversion of the bromide into alkoxy derivatives, the conversionmay be carried out by reacting the bromide with an excess of sodiummethoxide in methanol with cuprous salts, such as copper I bromide,copper I iodide, and copper I cyanide. The temperature may be carriedout at temperatures of between ambient and 175° but most likely will bearound 115° C. or 100° C. The reaction may be run in a pressure vesselor sealed tube to prevent escape of volatiles such as methanol. Thepreferred conditions utilize 3 eq of sodium methoxide in methanol, CuBras the reaction catalyst (0.2 to 3 equivalents with the preferred being1 eq or less), and a reaction temperature of 115° C. The reaction iscarried out in a sealed tube or sealed reaction vessel. The conversionof the bromide into alkoxy derivatives may also be carried out accordingto procedures described in Palucki, M.; Wolfe, J. P.; Buchwald, S. L.;J. Am. Chem. Soc. 1997, 119(14), 3395-3396; Yamato, T.; Komine, M.;Nagano, Y.; Org. Prep. Proc. Int. 1997, 29(3), 300-303; Rychnovsky, S.D.; Hwang, K.; J. Org. Chem. 1994, 59(18), 5414-5418. Conversion of thebromide to the fluoro derivative (Step U, Scheme 2A) may be accomplishedaccording to Antipin, I. S.; Vigalok, A. I.; Konovalov, A. I.; Zh. Org.Khim. 1991, 27(7), 1577-1577; and Uchibori, Y.; Umeno, M.; Seto, H.;Qian, Z.; Yoshioka, H.; Synlett. 1992, 4, 345-346. Conversion of thebromide to the chloro derivative (Step U, Scheme 2A) may be accomplishedaccording to procedures described in Gilbert, E. J.; Van Vranken, D. L.;J. Am. Chem. Soc. 1996, 118(23), 5500-5501; Mongin, F.; Mongin, 0.;Trecourt, F.; Godard, A.; Queguiner, G.; Tetrahedron Lett. 1996, 37(37),6695-6698; and O'Connor, K. J.; Burrows, C. J.; J. Org. Chem. 1991,56(3), 1344-1346. Steps V, W and X of Scheme 2A are carried outaccording to the procedures previously described for Steps B, C, and Dof Scheme 1, respectively. The steps of Scheme 2A may be carried out ina different order as shown in Scheme 2B and Scheme 2C.

Scheme 3 shows the synthesis of 4-azaindole derivatives 1b-5b,5-azaindole derivatives 1c-5c, and 7-azaindole derivatives 1d-5d. Themethods used to synthesize 1b-5b, 1c-5c, and 1d-5d are the same methodsdescribed for the synthesis of 1a-5a as described in Scheme 1. It isunderstood, for the purposes of Scheme 3, that 1b is used to synthesize2b-5b, 1c provides 2c-5c and 1d provides 2d-5d.

The compounds where there is a single carbonyl between the azaindole andgroup W can be prepared by the method of Kelarev, V. I.; Gasanov, S.Sh.; Karakhanov, R. A.; Polivin, Yu. N.; Kuatbekova, K. P.; Panina, M.E.; Zh. Org. Khim 1992, 28(12), 2561-2568. In this method azaindoles arereacted with trichloroacetyl chloride in pyridine and then subsequentlywith KOH in methanol to provide the 3-carbomethoxy azaindoles shown inScheme 4 which can then be hydrolyzed to the acid and carried throughthe coupling sequence with HW(C═O)A to provide the compounds of FormulaI wherein a single carbonyl links the azaindole moiety and group W.

An alternative method for carrying out the sequence outlined in stepsB-D (shown in Scheme 5) involves treating an azaindole, such as 11,obtained by procedures described in the literature or from commercialsources, with MeMgI and ZnCl₂, followed by the addition of ClCOCOCl(oxalyl chloride) in either THF or Et₂O to afford a mixture of a glyoxylchloride azaindole, 12a, and an acyl chloride azaindole, 12b. Theresulting mixture of glyoxyl chloride azaindole and acyl chlorideazaindole is then coupled with mono-benzoylated piperazine derivativesunder basic conditions to afford the products of step D as a mixture ofcompounds, 13a and 13b, where either one or two carbonyl groups link theazaindole and group W. Separation via chromatographic methods which arewell known in the art provides the pure 13a and 13b. This sequence issummarized in Scheme 5, below.

Scheme 6 depicts a general method for modifying the substituent A.Coupling of H—W—C(O)OtBu using the conditions described previously for Win Scheme 1, Step D provides Boc protected intermediate, 15.Intermediate 15 is then deprotected by treatment with an acid such asTFA, hydrochloric acid or formic acid using standard solvents oradditives such as CH₂Cl₂, dioxane, or anisole and temperatures between−78° C. and 100° C. Other acids such as aq hydrochloric or perchloricmay also be used for deprotection. Alternatively other nitrogenprotecting groups on W such as Cbz or TROC, may be utilized and could beremoved via hydrogenation or treatment with zinc respectively. A stablesilyl protecting group such as phenyl dimethylsilyl could also beemployed as a nitrogen protecting group on W and can be removed withfluoride sources such as tetrabutylammonium fluoride. Finally, the freeamine is coupled to acid A-C(O)OH using standard amine-acid couplingconditions such as those used to attach group W or as shown below foramide formation on positions R₁-R₄ to provide compound 16.

Some specific examples of general methods for preparing functionalizedazaindoles or for interconverting functionality on aza indoles whichwill be useful for preparing the compounds of this invention are shownin the following sections for illustrative purposes. It should beunderstood that this invention covers substituted 4, 5, 6, and 7azaindoles and that the methodology shown below may be applicable to allof the above series while other shown below will be specific to one ormore. A typical practioner of the art can make this distinction when notspecifically delineated. Many methods are intended to be applicable toall the series, particularly functional group installations orinterconversions. For example, a general strategy for providing furtherfunctionality of this invention is to position or install a halide suchas bromo, chloro, or iodo, aldehyde, cyano, or a carboxy group on theazaindole and then to convert that functionality to the desiredcompounds. In particular, conversion to substituted heteroaryl, aryl,and amide groups on the ring are of particular interest.

General routes for functionalizing azaindole rings are shown in Schemes7, 8 and 9. As depicted in Scheme 7, the azaindole, 17, can be oxidizedto the corresponding N-oxide derivative, 18, by using mCPBA(meta-Chloroperbenzoic Acid) in acetone or DMF (eq. 1, Harada et al, Ref29 and Antonini et al, Ref 34). The N-oxide, 18, can be converted to avariety of substituted azaindole derivatives by using well documentedreagents such as phosphorus oxychloride (POCl₃) (eq. 2, Schneller et al,Ref 30), tetramethylammonium fluoride (Me₄NF) (eq. 3), Grignard reagentsRMgX (R=alkyl or aryl, X=Cl, Br or I) (eq. 4, Shiotani et al, Ref 31),trimethylsilyl cyanide (TMSCN) (eq. 5, Minakata et al, Ref 32) or Ac₂O(eq. 6, Klemm et al, Ref 33). Under such conditions, a chlorine (in 19),fluorine (in 20), nitrile (in 22), alkyl (in 21), aromatic (in 21) orhydroxyl group (in 24) can be introduced to the pyridine ring. Nitrationof azaindole N-oxides results in introduction of a nitro group toazaindole ring, as shown in Scheme 8 (eq. 7, Antonini et al, Ref 34).The nitro group can subsequently be displaced by a variety ofnucleophilic agents, such as OR, NR¹R² or SR, in a well establishedchemical fashion (eq. 8, Regnouf De Vains et al, Ref 35(a), Miura et al,Ref 35(b), Profft et al, Ref 35(c)). The resulting N-oxides, 26, arereadily reduced to the corresponding azaindole, 27, using phosphorustrichloride (PCl₃) (eq. 9, Antonini et al, Ref 0.34 and Nesi et al, Ref36). Similarly, nitro-substituted N-oxide, 25, can be reduced to theazaindole, 28, using phosphorus trichloride (eq. 10). The nitro group ofcompound 28 can be reduced to either a hydroxylamine (NHOH), as in 29,(eq. 11, Walser et al, Ref 37(a) and Barker et al, Ref 37(b)) or anamino (NH₂) group, as in 30, (eq. 12, Nesi et al, Ref 36 and Ayyangar etal, Ref 38) by carefully selecting different reducing conditions.

The alkylation of the nitrogen atom at position 1 of the azaindolederivatives can be achieved using NaH as the base, DMF as the solventand an alkyl halide or sulfonate as alkylating agent, according to aprocedure described in the literature (Mahadevan et al, Ref 39) (Scheme9).

In the general routes for substituting the azaindole ring describedabove, each process can be applied repeatedly and combinations of theseprocesses is permissible in order to provide azaindoles incorporatingmultiple substituents. The application of such processes providesadditional compounds of Formula I.

The synthesis of 4-aminoazaindoles which are useful precursors for 4, 5,and/or 7-substituted azaindoles is shown in Scheme 10 above.

The synthesis of 3,5-dinitro-4-methylpyridine, 32, is described in thefollowing two references by Achremowicz et. al.: Achremowicz, Lucjan.Pr. Nauk. Inst. Chem. Org. Fiz. Politech. Wroclaw. 1982, 23, 3-128;Achremowicz, Lucjan. Synthesis 1975, 10, 653-4. In the first step ofScheme 10, the reaction with dimethylformamide dimethyl acetal in aninert solvent or neat under conditions for forming Batcho-Leimgruberprecursors provides the cyclization precursor, 33, as shown. Althoughthe step is anticipated to work as shown, the pyridine may be oxidizedto the N-oxide prior to the reaction using a peracid such as MCPBA or amore potent oxidant like meta-trifluoromethyl or meta nitro peroxybenzoic acids. In the second step of Scheme 10, reduction of the nitrogroup using for example hydrogenation over Pd/C catalyst in a solventsuch as MeOH, EtOH, or EtOAc provides the cyclized product, 34.Alternatively the reduction may be carried out using tin dichloride andHCl, hydrogenation over Raney nickel or other catalysts, or by usingother methods for nitro reduction such as described elsewhere in thisapplication.

The amino indole, 34, can now be converted to compounds of Formula Ivia, for example, diazotization of the amino group, and then conversionof the diazonium salt to the fluoride, chloride or alkoxy group. See thediscussion of such conversions in the descriptions for Schemes 17 and18. The conversion of the amino moiety into desired functionality couldthen be followed by installation of the oxoacetopiperazine moiety by thestandard methodology described above. 5 or 7-substitution of theazaindole can arise from N-oxide formation at position 6 and subsequentconversion to the chloro via conditions such as POCl₃ in chloroform,acetic anhydride followed by POCl₃ in DMF, or alternatively TsCl in DMF.Literature references for these and other conditions are provided insome of the later Schemes in this application. The synthesis of4-bromo-7-hydroxy or protected hydroxy-4-azaindole is described below asthis is a useful precursor for 4 and/or 7 substituted 6-aza indoles.

The synthesis of 5-bromo-2-hydroxy-4-methyl-3-nitro pyridine, 35, may becarried out as described in the following reference: Betageri, R.;Beaulieu, P. L.; Llinas-Brunet, M; Ferland, J. M.; Cardozo, M.; Moss,N.; Patel, U.; Proudfoot, J. R. PCT Int. Appl. WO 9931066, 1999.Intermediate 36 is prepared from 35 according to the method as describedfor Step 1 of Scheme 10. PG is an optional hydroxy protecting group suchas triallylsilyl or the like. Intermediate 37 is then prepared from 36by the selective reduction of the nitro group in the presence of bromideand subsequent cyclization as described in the second step of Scheme 10.Fe(OH)₂ in DMF with catalytic tetrabutylammonium bromide can also beutilized for the reduction of the nitro group. The bromide may then beconverted to fluoride via displacement with fluoride anions or to othersubstituents. The compounds are then converted to compounds of Formula Ias above.

An alternate method for preparing substituted 6-azaindoles is shownbelow in Schemes 12 and 13. It should be recognized that slightmodifications of the route depicted below are possible. For example,acylation reactions of the 3 position of what will become the azaindolefive membered ring, prior to aromatization of the azaindole, may becarried out in order to obtain higher yields. In addition to apara-methoxybenzyl group (PMB), a benzyl group can be carried throughthe sequence and removed during azaindole formation by using TsOH,p-Chloranil, in benzene as the oxidant if DDQ is not optimal. The benzylintermediate, 38, has been described by Ziegler et al. in J. Am. Chem.Soc. 1973, 95(22), 7458. The transformation of 38 to 40 is analogous tothe transformation described in Heterocycles 1984, 22, 2313.

Scheme 13 describes various transformations of intermediate 40 whichultimately provide compounds of Formula I. The conversions of the phenolmoiety to other functionality at position 4 (R₂ position in Scheme 13)may be carried out by the following methods: 1) conversion of a phenolto methoxy group with silver oxide and MeI or diazomethane; 2)conversion of a phenolic hydroxy group to chloro using cat ZnCl₂, andN,N dimethylaniline in CH₂Cl₂ or PCl₅ and POCl₃ together; 3) conversionof a phenolic hydroxy group to fluoro using diethylamine-SF₃ as in Org.Prep. Proc. Int. 1992, 24(1), 55-57. The method described in EP 427603,1991, using the chloroformate and HF will also be useful. Othertransformations are possible. For example the phenol can be converted toa triflate by standard methods and used in coupling chemistriesdescribed later in this application.

Step E. Scheme 14 depicts the nitration of an azaindole, 41, (R₂═H).Numerous conditions for nitration of the azaindole may be effective andhave been described in the literature. N₂O₅ in nitromethane followed byaqueous sodium bisulfate according to the method of Bakke, J. M.; Ranes,E.; Synthesis 1997, 3, 281-283 could be utilized. Nitric acid in aceticmay also be employed as described in Kimura, H.; Yotsuya, S.; Yuki, S.;Sugi, H.; Shigehara, I.; Haga, T.; Chem. Pharm. Bull. 1995, 43(10),1696-1700. Sulfuric acid followed by nitric acid may be employed as inRuefenacht, K.; Kristinsson, H.; Mattern, G.; Helv Chim Acta 1976, 59,1593. Coombes, R. G.; Russell, L. W.; J. Chem. Soc., Perkin Trans. 11974, 1751 describes the use of a Titatanium based reagent system fornitration. Other conditions for the nitration of the azaindole can befound in the following references: Lever, O. W. J.; Werblood, H. M.;Russell, R. K.; Synth. Comm. 1993, 23(9), 1315-1320; Wozniak, M.; VanDer Plas, H. C.; J. Heterocycl Chem. 1978, 15, 731.

Step F

As shown above in Scheme 15, Step F, substituted azaindoles containing achloride, bromide, iodide, triflate, or phosphonate undergo couplingreactions with a boronate (Suzuki type reactions) or a stannane toprovide substituted azaindoles. Stannanes and boronates are prepared viastandard literature procedures or as described in the experimentalsection of this application. The substitututed indoles may undergo metalmediated coupling to provide compounds of Formula I wherein R₄ is aryl,heteroaryl, or heteroalicyclic for example. The bromoazaindoleintermediates, (or azaindole triflates or iodides) may undergoStille-type coupling with heteroarylstannanes as shown in Scheme 15.Conditions for this reaction are well known in the art and the followingare three example references a) Farina, V.; Roth, G. P. Recent advancesin the Stille reaction; Adv. Met.-Org. Chem. 1996, 5, 1-53. b) Farina,V.; Krishnamurthy, V.; Scott, W. J. The Stille reaction; Org. React. (N.Y.) 1997, 50, 1-652. and c) Stille, J. K. Angew. Chem. Int. Ed. Engl.1986, 25, 508-524. Other references for general coupling conditions arealso in the reference by Richard C. Larock Comprehensive OrganicTransformations 2nd Ed. 1999, John Wiley and Sons New York. All of thesereferences provide numerous conditions at the disposal of those skilledin the art in addition to the specific examples provided in Scheme 15and in the specific embodiments. It can be well recognized that anindole stannane could also couple to a heterocyclic or aryl halide ortriflate to construct compounds of Formula I. Suzuki coupling (NorioMiyaura and Akiro Suzuki Chem Rev. 1995, 95, 2457.) between a triflate,bromo, or chloro azaindole intermediate and a suitable boronate couldalso be employed and some specific examples are contained in thisapplication. Palladium catalyzed couplings of stannanes and boronatesbetween chloro azaindole intermediates are also feasible and have beenutilized extensively for this invention. Preferred procedures forcoupling of a chloro azaindole and a stannane employ dioxane,stoichiometric or an excess of the tin reagent (up to 5 equivalents),0.1 to 1 eq of Palladium (0) tetrakis triphenyl phosphine in dioxaneheated for 5 to 15 h at 110 to 120°. Other solvents such as DMF, THF,toluene, or benzene could be employed. Preferred procedures for Suzukicoupling of a chloro azaindole and a boronate employ 1:1 DMF water assolvent, 2 equivalents of potassium carbonate as base stoichiometric oran excess of the boron reagent (up to 5 equivalents), 0.1 to 1 eq ofPalladium (0) tetrakis triphenyl phosphine heated for 5 to 15 h at 110to 120°. If standard conditions fail new specialized catalysts andconditions can be employed. Some references (and the references therein)describing catalysts which are useful for coupling with aryl andheteroaryl chlorides are:

Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122(17),4020-4028; Varma, R. S.; Naicker, K. P. Tetrahedron Lett. 1999, 40(3),439-442; Wallow, T. I.; Novak, B. M. J. Org. Chem. 1994, 59(17), 5034-7;Buchwald, S.; Old, D. W.; Wolfe, J. P.; Palucki, M.; Kamikawa, K.;Chieffi, A.; Sadighi, J. P.; Singer, R. A.; Ahman, J PCT Int. Appl. WO0002887 2000; Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999,38(23), 3415; Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L.J. Am. Chem. Soc. 1999, 121(41), 9550-9561; Wolfe, J. P.; Buchwald, S.L. Angew. Chem., Int. Ed. 1999, 38(16), 2413-2416; Bracher, F.;Hildebrand, D.; Liebigs Ann. Chem. 1992, 12, 1315-1319; and Bracher, F.;Hildebrand, D.; Liebigs Ann. Chem. 1993, 8, 837-839.

Alternatively, the boronate or stannane may be formed on the azaindolevia methods known in the art and the coupling performed in the reversemanner with aryl or heteroaryl based halogens or triflates.

Known boronate or stannane agents could be either purchased fromcommercial resources or prepared following disclosed documents.Additional examples for the preparation of tin reagents or boronatereagents are contained in the experimental section.

Novel stannane agents could be prepared from one of the followingroutes.

Boronate reagents are prepared as described in reference 71. Reaction oflithium or Grignard reagents with trialkyl borates generates boronates.Alternatively, Palladium catalyzed couplings of alkoxy diboron or alkyldiboron reagents with aryl or heteroaryl halides can provide boronreagents for use in Suzuki type couplings. Some example conditions forcoupling a halide with (MeO)BB(OMe)2 utilize PdCl2 (dppf), KOAc, DMSO,at 80° C. until reaction is complete when followed by TLC or HPLCanalysis.

Related examples are provided in the following experimental section.

Methods for direct addition of aryl or heteroaryl organometallicreagents to alpha chloro nitrogen containing heterocyles or the N-oxidesof nitrogen containing heterocycles are known and applicable to theazaindoles. Some examples are Shiotani et. Al. J. Heterocyclic Chem.1997, 34(3), 901-907; Fourmigue et. al. J. Org. Chem. 1991, 56(16),4858-4864.

Direct displacements to install amine or N linked heteroarylsubstituents can also be used to prepare compounds of Formula I. Asshown in Schemes 15aa and 15bb, a mixture of halo-indole orhalo-azaindole intermediate, 1-2 equivalents of copper powder, with 1equivalent preferred for the 4-F,6-azaindole series and 2 equivalentsfor the 4-methoxy, 6-azaindole series; 1-2 equivalents of potassiumcarbonate, with 1 equivalent preferred for the 4-F,6-azaindole seriesand 2 equivalents for the 4-methoxy,6-azaindole series; and a 2-30equivalents of the corresponding heterocyclic reagent, with 10equivalents preferred; was heated at 135-160° C. for 4 to 9 hours, with5 hours at 160° C. preferred for the 4-F,6-azaindole series and 7 hoursat 135° C. preferred for the 4-methoxy,6-azaindole series. The reactionmixture was cooled to room temperature and filtered through filterpaper. The filtrate was diluted with methanol and purified either bypreparative HPLC or silica gel. In many cases no chromatography isnecessary, the product can be obtained by crystallization with methanol.

Alternatively, the installation of amines or N linked heteroaryls may becarried out by heating 1 to 40 equivalents of the appropriate amine andan equivalent of the appropriate aza indole chloride, bromide or iodidewith copper bronze (from 0.1 to 10 equivalents (preferably about 2equivalents) and from 1 to 10 equivalents of finely pulverized potassiumhydroxide (preferably about 2 equivalents). Temperatures of 120° to 200°may be employed with 140-160° generally preferred. For volatile startingmaterials a sealed reactor may be employed. The reaction is mostcommonly used when the halogen being displaced is at the 7-position of a6-aza (or 4-azaindole, not shown) but the method can work in the5-azaseries or when the halogen is at a different position (4-7 positionpossible). As shown above the reaction can be employed on azaindolesunsubstituted at position 3 or intermediates which contain thedicarbonyl or the intact dicarbonyl piperazine urea or thioureascontained in compounds of formula I.

The preparation of a key aldehyde intermediate, 43, using a procedureadapted from the method of Gilmore et. Al. Synlett 1992, 79-80. Is shownin Scheme 16 above. The aldehyde substituent is shown only at the R₄position for the sake of clarity, and should not be considered as alimitation of the methodology. The bromide or iodide intermediate isconverted into an aldehyde intermediate, 43, by metal-halogen exchangeand subsequent reaction with dimethylformamide in an appropriate aproticsolvent. Typical bases used include, but are not limited to, alkyllithium bases such as n-butyl lithium, sec butyl lithium or tert butyllithium or a metal such as lithium metal. A preferred aprotic solvent isTHF. Typically the transmetallation is initiated at −78° C. The reactionmay be allowed to warm to allow the transmetalation to go to completiondepending on the reactivity of the bromide intermediate. The reaction isthen recooled to −78° C. and allowed to react with dimethylformamide.(allowing the reaction to warm may be required to enable completereaction) to provide an aldehyde which is elaborated to compounds ofFormula I. Other methods for introduction of an aldehyde group to formintermediates of formula 43 include transition metal catalyzedcarbonylation reactions of suitable bromo, trifluoromethane sulfonyl, orstannyl azaindoles. Alternative the aldehydes can be introduced byreacting indolyl anions or indolyl Grignard reagents with formaldehydeand then oxidizing with MnO₂ or TPAP/NMO or other suitable oxidants toprovide intermediate 43.

The methodology described in T. Fukuda et. al. Tetrahedron 1999, 55,9151 and M. Iwao et. Al. Heterocycles 1992, 34(5), 1031 provide methodsfor preparing indoles with substituents at the 7-position. The Fukudareferences provide methods for functionalizing the C-7 position ofindoles by either protecting the indole nitrogen with 2,2-diethylpropanoyl group and then deprotonating the 7-position with sec/Buli inTMEDA to give an anion. This anion may be quenched with DMF,formaldehyde, or carbon dioxide to give the aldehyde, benzyl alcohol, orcarboxylic acid respectively and the protecting group removed withaqueous t butoxide. Similar transformations can be achieved byconverting indoles to indoline, lithiation at C-7 and then reoxidationto the indole such as described in the Iwao reference above. Theoxidation level of any of these products may be adjusted by methods wellknown in the art as the interconversion of alcohol, aldehyde, and acidgroups has been well studied. It is also well understood that a cyanogroup can be readily converted to an aldehyde. A reducing agent such asDIBALH in hexane such as used in Weyerstahl, P.; Schlicht, V.; LiebigsAnn/Recl. 1997, 1, 175-177 or alternatively catecholalane in THF such asused in Cha, J. S.; Chang, S. W.; Kwon, O. O.; Kim, J. M.; Synlett.1996, 2, 165-166 will readily achieve this conversion to provideintermediates such as 44 (Scheme 16). Methods for synthesizing thenitriles are shown later in this application. It is also well understoodthat a protected alcohol, aldehyde, or acid group could be present inthe starting azaindole and carried through the synthetic steps to acompound of Formula I in a protected form until they can be convertedinto the desired substituent at R₁ through R₄. For example, a benzylalcohol can be protected as a benzyl ether or silyl ether or otheralcohol protecting group; an aldehyde may be carried as an acetal, andan acid may be protected as an ester or ortho ester until deprotectionis desired and carried out by literature methods.

Step G. Step 1 of Scheme 17 shows the reduction of a nitro group on 45to the amino group of 46. Although shown on position 4 of the azaindole,the chemistry is applicable to other nitro isomers. The proceduredescribed in Ciurla, H.; Puszko, A.; Khim Geterotsikl Soedin 1996, 10,1366-1371 uses hydrazine Raney-Nickel for the reduction of the nitrogroup to the amine Robinson, R. P.; DonahueO, K. M.; Son, P. S.; Wagy,S. D.; J. Heterocycl. Chem. 1996, 33(2), 287-293 describes the use ofhydrogenation and Raney Nickel for the reduction of the nitro group tothe amine Similar conditions are described by Nicolai, E.; Claude, S.;Teulon, J. M.; J. Heterocycl. Chem. 1994, 31(1), 73-75 for the sametransformation. The following two references describe sometrimethylsilyl sulfur or chloride based reagents which may be used forthe reduction of a nitro group to an amine Hwu, J. R.; Wong, F. F.;Shiao, M. J.; J. Org. Chem. 1992, 57(19), 5254-5255; Shiao, M. J.; Lai,L. L.; Ku, W. S.; Lin, P. Y.; Hwu, J. R.; J. Org. Chem. 1993, 58(17),4742-4744.

Step 2 of Scheme 17 describes general methods for conversion of aminogroups on azaindoles into other functionality. Scheme 18 also depictstransformations of an amino azaindole into various intermediates andcompounds of Formula I.

The amino group at any position of the azaindole, such as 46 (Scheme17), may be converted to a hydroxy group using sodium nitrite, sulfuricacid, and water via the method of Klemm, L. H.; Zell, R.; J. Heterocycl.Chem. 1968, 5, 773. Bradsher, C. K.; Brown, F. C.; Porter, H. K.; J. Am.Chem. Soc. 1954, 76, 2357 describes how the hydroxy group may bealkylated under standard or Mitsonobu conditions to form ethers. Theamino group may be converted directly into a methoxy group bydiazotization (sodium nitrite and acid) and trapping with methanol.

The amino group of an azaindole, such as 46, can be converted to fluorovia the method of Sanchez using HPF₆, NaNO₂, and water by the methoddescribed in Sanchez, J. P.; Gogliotti, R. D.; J. Heterocycl. Chem.1993, 30(4), 855-859. Other methods useful for the conversion of theamino group to fluoro are described in Rocca, P.; Marsais, F.; Godard,A.; Queguiner, G.; Tetrahedron Lett. 1993, 34(18), 2937-2940 andSanchez, J. P.; Rogowski, J. W.; J. Heterocycl. Chem. 1987, 24, 215.

The amino group of the azaindole, 46, can also be converted to achloride via diazotization and chloride displacement as described inCiurla, H.; Puszko, A.; Khim Geterotsikl Soedin 1996, 10, 1366-1371 orthe methods in Raveglia, L. F.; Giardina, G. A.; Grugni, M.; Rigolio,R.; Farina, C.; J. Heterocycl. Chem. 1997, 34(2), 557-559 or the methodsin Matsumoto, J. I.; Miyamoto, T.; Minamida, A.; Mishimura, Y.; Egawa,H.; Mishimura, H.; J. Med. Chem. 1984, 27(3), 292; or as in Lee, T. C.;Salemnick, G.; J. Org. Chem. 1975, 24, 3608.

The amino group of the azaindole, 46, can also be converted to a bromidevia diazotization and displacement by bromide as described in Raveglia,L. F.; Giardina, G. A.; Grugni, M.; Rigolio, R.; Farina, C.; J.Heterocycl. Chem. 1997, 34(2), 557-559; Talik, T.; Talik, Z.;Ban-Oganowska, H.; Synthesis 1974, 293; and Abramovitch, R. A.; Saha,M.; Can. J. Chem. 1966, 44, 1765.

The preparation of 4-amino 4-azaindole and 7-methyl-4-azaindole isdescribed by Mahadevan, I.; Rasmussen, M. J. Heterocycl. Chem. 1992,29(2), 359-67. The amino group of the 4-amino 4-azaindole can beconverted to halogens, hydroxy, protected hydroxy, triflate, asdescribed above in Schemes 17-18 for the 4-amino compounds or by othermethods known in the art. Protection of the indole nitrogen of the7-methyl-4-azaindole via acetylation or other strategy followed byoxidation of the 7-methyl group with potassium permanganate or chromicacid provides the 7-acid/4-N-oxide. Reduction of the N-oxide, asdescribed below, provides an intermediate from which to install varioussubstituents at position R₄. Alternatively the parent 4-azaindole whichwas prepared as described in Mahadevan, I.; Rasmussen, M. J. Heterocycl.Chem. 1992, 29(2), 359-67 could be derivatized at nitrogen to providethe 1-(2,2-diethylbutanoyl)azaindole which could then be lithiated usingTMEDA/sec BuLi as described in T. Fukuda et. Al. Tetrahedron 1999, 55,9151-9162; followed by conversion of the lithio species to the7-carboxylic acid or 7-halogen as described. Hydrolysis of the N-amideusing aqueous tert-butoxide in THF regenerates the free NH indole whichcan now be converted to compounds of Formula I. The chemistry used tofunctionalize position 7 can also be applied to the 5 and 6 indoleseries.

Scheme 19 shows the preparation of a 7-chloro-4-azaindole, 50, which canbe converted to compounds of Formula I by the chemistry previouslydescribed, especially the palladium catalyzed tin and boron basedcoupling methodology described above. The chloro nitro indole, 49, iscommercially available or can be prepared from 48 according to themethod of Delarge, J.; Lapiere, C. L. Pharm. Acta Helv. 1975, 50(6),188-91.

Scheme 20, below, shows another synthetic route to substituted 4-azaindoles. The 3-aminopyrrole, 51, was reacted to provide thepyrrolopyridinone, 52, which was then reduced to give the hydroxyazaindole, 53. The pyrrolo[2,3-b]pyridines described were preparedaccording to the method of Britten, A. Z.; Griffiths, G. W. G. Chem.Ind. (London) 1973, 6, 278. The hydroxy azaindole, 53, can then beconverted to the triflate then further reacted to provide compounds ofFormula I.

The following references describe the synthesis of 7-halo or 7carboxylic acid, or 7-amido derivatives of 5-azaindoline which can beused to construct compounds of Formula I. Bychikhina, N. N.; Azimov, V.A.; Yakhontov, L. N. Khim. Geterotsikl. Soedin. 1983, 1, 58-62;Bychikhina, N. N.; Azimov, V. A.; Yakhontov, L. N. Khim. Geterotsikl.Soedin. 1982, 3, 356-60; Azimov, V. A.; Bychikhina, N. N.; Yakhontov, L.N. Khim. Geterotsikl. Soedin. 1981, 12, 1648-53; Spivey, A. C.; Fekner,T.; Spey, S. E.; Adams, H. J. Org. Chem. 1999, 64(26), 9430-9443;Spivey, A. C.; Fekner, T.; Adams, H. Tetrahedron Lett. 1998, 39(48),8919-8922. The methods described in Spivey et al. (preceding tworeferences) for the preparation of 1-methyl-7-bromo-4-azaindoline can beused to prepare the 1-benzyl-7-bromo-4-azaindoline, 54, shown below inScheme 21. This can be utilized in Stille or Suzuki couplings to provide55, which is deprotected and dehydrogenated to provide 56. Other usefulazaindole intermediates, such as the cyano derivatives, 57 and 58, andthe aldehyde derivatives, 59 and 60, can then be further elaborated tocompounds of Formula I.

Alternatively the 7-functionalized 5-azaindole derivatives may beobtained by functionalization using the methodologies of T. Fukuda et.al. Tetrahedron 1999, 55, 9151 and M. Iwao et. Al. Heterocycles 1992,34(5), 1031described above for the 4 or 6 azaindoles. The 4 or 6positions of the 5 aza indoles can be functionalized by using theazaindole N-oxide.

The conversion of indoles to indolines is well known in the art and canbe carried out as shown or by the methods described in Somei, M.; Saida,Y.; Funamoto, T.; Ohta, T. Chem. Pharm. Bull. 1987, 35(8), 3146-54; M.Iwao et. Al. Heterocycles 1992, 34(5), 1031; andAkagi, M.; Ozaki, K.Heterocycles 1987, 26(1), 61-4.

The preparation of azaindole oxoacetyl or oxo piperidines withcarboxylic acids can be carried out from nitrile, aldehyde, or anionprecursors via hydrolysis, oxidation, or trapping with CO₂ respectively.As shown in the Scheme 22, Step 1, or the scheme below step a12 onemethod for forming the nitrile intermediate, 62, is by cyanidedisplacement of a halide in the aza-indole ring. The cyanide reagentused can be sodium cyanide, or more preferably copper or zinc cyanide.The reactions may be carried out in numerous solvents which are wellknown in the art. For example DMF is used in the case of copper cyanide.Additional procedures useful for carrying out step 1 of Scheme 24 areYamaguchi, S.; Yoshida, M.; Miyajima, I.; Araki, T.; Hirai, Y.; J.Heterocycl. Chem. 1995, 32(5), 1517-1519 which describes methods forcopper cyanide; Yutilov, Y. M.; Svertilova, I. A.; Khim GeterotsiklSoedin 1994, 8, 1071-1075 which utilizes potassium cyanide; and Prager,R. H.; Tsopelas, C.; Heisler, T.; Aust. J. Chem. 1991, 44 (2), 277-285which utilizes copper cyanide in the presence of MeOS(O)₂F. The chlorideor more preferably a bromide on the azaindole may be displaced by sodiumcyanide in dioxane via the method described in Synlett. 1998, 3,243-244. Alternatively, Nickel dibromide, Zinc, and triphenyl phosphinein can be used to activate aromatic and heteroaryl chlorides todisplacement via potassium cyanide in THF or other suitable solvent bythe methods described in Eur. Pat. Appl., 831083, 1998.

The conversion of the cyano intermediate, 62, to the carboxylic acidintermediate, 63, is depicted in step 2, Scheme 22 or in step a12,Scheme 23. Many methods for the conversion of nitriles to acids are wellknown in the art and may be employed. Suitable conditions for step 2 ofScheme 22 or the conversion of intermediate 65 to intermediate 66 belowemploy potassium hydroxide, water, and an aqueous alcohol such asethanol. Typically the reaction must be heated at refluxing temperaturesfor one to 100 h. Other procedures for hydrolysis include thosedescribed in:

Shiotani, S.; Taniguchi, K.; J. Heterocycl. Chem. 1997, 34(2), 493-499;Boogaard, A. T.; Pandit, U. K.; Koomen, G.-J.; Tetrahedron 1994, 50(8),2551-2560; Rivalle, C.; Bisagni, E.; Heterocycles 1994, 38(2), 391-397;Macor, J. E.; Post, R.; Ryan, K.; J. Heterocycl. Chem. 1992, 29(6),1465-1467.

The acid intermediate, 66 (Scheme 23), may then be esterified usingconditions well known in the art. For example, reaction of the acid withdiazomethane in an inert solvent such as ether, dioxane, or THF wouldgive the methyl ester. Intermediate 67 may then be converted tointermediate 68 according to the procedure described in Scheme 2.Intermediate 68 may then be hydrolyzed to provide intermediate 69.

As shown in Scheme 24, step a13 another preparation of theindoleoxoacetylpiperazine 7-carboxylic acids, 69, is carried out byoxidation of the corresponding 7-carboxaldehyde, 70. Numerous oxidantsare suitable for the conversion of aldehyde to acid and many of theseare described in standard organic chemistry texts such as: Larock,Richard C., Comprehensive organic transformations: a guide to functionalgroup preparations 2^(nd) ed. New York: Wiley-VCH, 1999. One preferredmethod is the use of silver nitrate or silver oxide in a solvent such asaqueous or anhydrous methanol at a temperature of −25° C. or as high asreflux. The reaction is typically carried out for one to 48 h and istypically monitored by TLC or LC/MS until complete conversion of productto starting material has occurred. Alternatively, KmnO₄ or CrO₃/H₂SO₄could be utilized.

Scheme 25 gives a specific example of the oxidation of an aldehydeintermediate, 70a, to provide the carboxylic acid intermediate, 69a.

Alternatively, intermediate 69 can be prepared by the nitrile method ofsynthesis carried out in an alternative order as shown in Scheme 26. Thenitrile hydrolyis step can be delayed and the nitrile carried throughthe synthesis to provide a nitrile which can be hydrolyzed to providethe free acid, 69, as above.

Step H. The direct conversion of nitriles, such as 72, to amides, suchas 73, shown in Scheme 27, Step H, can be carried out using theconditions as described in Shiotani, S.; Taniguchi, K.; J. Heterocycl.Chem. 1996, 33(4), 1051-1056 (describes the use of aqueous sulfuricacid); Memoli, K. A.; Tetrahedron Lett. 1996, 37(21), 3617-3618;Adolfsson, H.; Waernmark, K.; Moberg, C.; J. Org. Chem. 1994, 59(8),2004-2009; and El Hadri, A.; Leclerc, G.; J. Heterocycl. Chem. 1993,30(3), 631-635.

Step I. For NH2

Shiotani, S.; Taniguchi, K.; J. Heterocycl. Chem. 1997, 34(2), 493-499;Boogaard, A. T.; Pandit, U. K.; Koomen, G.-J.; Tetrahedron 1994, 50(8),2551-2560; Rivalle, C.; Bisagni, E.; Heterocycles 1994, 38(2), 391-397;Macor, J. E.; Post, R.; Ryan, K.; J. Heterocycl. Chem. 1992, 29(6),1465-1467.

Step J.

The following scheme (28A) shows an example for the preparation of4-fluoro-7 substituted azaindoles from a known starting materials.References for the Bartoli indole synthesis were mentioned earlier. Theconditions for transformation to the nitriles, acids, aldeheydes,heterocycles and amides have also been described in this application.

Steps a16, a17, and a18 encompasses reactions and conditions for 1⁰, 2⁰and 3⁰ amide bond formation as shown in Schemes 28 and 29 which providecompounds such as those of Formula 73.

The reaction conditions for the formation of amide bonds encompass anyreagents that generate a reactive intermediate for activation of thecarboxylic acid to amide formation, for example (but not limited to),acyl halide, from carbodiimide, acyl iminium salt, symmetricalanhydrides, mixed anhydrides (including phosphonic/phosphinic mixedanhydrides), active esters (including silyl ester, methyl ester andthioester), acyl carbonate, acyl azide, acyl sulfonate and acyloxyN-phosphonium salt. The reaction of the indole carboxylic acids withamines to form amides may be mediated by standard amide bond formingconditions described in the art. Some examples for amide bond formationare listed in references 41-53 but this list is not limiting. Somecarboxylic acid to amine coupling reagents which are applicable are EDC,Diisopropylcarbodiimide or other carbodiimides, PyBop(benzotriazolyloxytris(dimethylamino) phosphonium hexafluorophosphate),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate (HBTU). A particularly useful method for azaindole7-carboxylic acid to amide reactions is the use of carbonyl imidazole asthe coupling reagent as described in reference 53. The temperature ofthis reaction may be lower than in the cited reference, from 80° C. (orpossibly lower) to 150° C. or higher. A more specific application isdepicted in Scheme 30.

The following four general methods provide a more detailed descriptionfor the preparation of indolecarboamides and these methods were employedfor the synthesis of compounds of Formula I.

Method 1:

To a mixture of an acid intermediate, such as 69, (1 equiv., 0.48 mmol),an appropriate amine (4 equiv.) and DMAP (58 mg, 0.47 mmol) dissolvedCH₂Cl₂ (1 mL) was added EDC (90 mg, 0.47 mmol). The resulting mixturewas shaken at rt for 12 h, and then evaporated in vacuo. The residue wasdissolved in MeOH, and subjected to preparative reverse phase HPLCpurification.

Method 2:

To a mixture of an appropriate amine (4 equiv.) and HOBT (16 mg, 0.12mmol) in THF (0.5 mL) was added an acid intermediate, such as 69, (25mg, 0.06 mmol) and NMM (50 μl, 0.45 mmol), followed by EDC (23 mg, 0.12mmol). The reaction mixture was shaken at rt for 12 h. The volatileswere evaporated in vacuo; and the residue dissolved in MeOH andsubjected to preparative reverse phase HPLC purification.

Method 3:

To a mixture of an acid intermediate, such as 69, (0.047 mmol), amine (4equiv.) and DEPBT (prepared according to Li, H.; Jiang, X. Ye, Y.; Fan,C.; Todd, R.; Goodman, M. Organic Letters 1999, 1, 91; 21 mg, 0.071mmol) in DMF (0.5 mL) was added TEA (0.03 mL, 0.22 mmol). The resultingmixture was shaken at rt for 12 h; and then diluted with MeOH (2 mL) andpurified by preparative reverse phase HPLC.

Method 4:

A mixture of an acid intermediate, such as 69, (0.047 mmol) and 8.5 mg(0.052 mmol) of 1,1-carbonyldiimidazole in anhydrous THF (2 mL) washeated to reflux under nitrogen. After 2.5 h, 0.052 mmol of amine wasadded and heating continued. After an additional period of 3-20 h atreflux, the reaction mixture was cooled and concentrated in vacuo. Theresidue was purified by chromatography on silica gel to provide acompound of Formula I.

In addition, the carboxylic acid may be converted to an acid chlorideusing reagents such as thionyl chloride (neat or in an inert solvent) oroxalyl chloride in a solvent such as benzene, toluene, THF, or CH₂Cl₂.The amides may alternatively, be formed by reaction of the acid chloridewith an excess of ammonia, primary, or secondary amine in an inertsolvent such as benzene, toluene, THF, or CH₂Cl₂ or with stoichiometricamounts of amines in the presence of a tertiary amine such astriethylamine or a base such as pyridine or 2,6-lutidine. Alternatively,the acid chloride may be reacted with an amine under basic conditions(Usually sodium or potassium hydroxide) in solvent mixtures containingwater and possibly a miscible co solvent such as dioxane or THF. Scheme25B depicts a typical preparation of an acid chloride and derivatizationto an amide of Formula I. Additionally, the carboxylic acid may beconverted to an ester preferably a methyl or ethyl ester and thenreacted with an amine. The ester may be formed by reaction withdiazomethane or alternatively trimethylsilyl diazomethane using standardconditions which are well known in the art. References and proceduresfor using these or other ester forming reactions can be found inreference 52 or 54.

Additional references for the formation of amides from acids are:Norman, M. H.; Navas, F. III; Thompson, J. B.; Rigdon, G. C.; J. Med.Chem. 1996, 39(24), 4692-4703; Hong, F.; Pang, Y.-P.; Cusack, B.;Richelson, E.; J. Chem. Soc., Perkin Trans 1 1997, 14, 2083-2088;Langry, K. C.; Org. Prep. Proc. Int. 1994, 26(4), 429-438; Romero, D.L.; Morge, R. A.; Biles, C.; Berrios-Pena, N.; May, P. D.; Palmer, J.R.; Johnson, P. D.; Smith, H. W.; Busso, M.; Tan, C.-K.; Voorman, R. L.;Reusser, F.; Althaus, I. W.; Downey, K. M.; et al.; J. Med. Chem. 1994,37(7), 999-1014; Bhattacharjee, A.; Mukhopadhyay, R.; Bhattacharjya, A.;Indian J. Chem., Sect B 1994, 33(7), 679-682.

Scheme 31 shows synthetic transformations on a chloro nitro azaindole.Step F-1 of Scheme 31 can be carried may be carried out according to thefollowing procedures: Yamaguchi, S.; Yoshida, M.; Miyajima, I.; Araki,T.; Hirai, Y.; J. Heterocycl. Chem. 1995, 32(5), 1517-1519;

Yutilov, Y. M.; Svertilova, I. A.; Khim Geterotsikl Soedin 1994, 8,1071-1075; and Prager, R. H.; Tsopelas, C.; Heisler, T.; Aust. J. Chem.1991, 44(2), 277-285. Step F-2 of Scheme 31 may be accomplishedaccording to the procedures set forth in: Ciurla, H.; Puszko, A.; KhimGeterotsikl Soedin 1996, 10, 1366-1371; Robinson, R. P.; Donahue, K. M.;Son, P. S.; Wagy, S. D.; J. Heterocycl. Chem. 1996, 33(2), 287-293;Nicolai, E.; Claude, S.; Teulon, J. M.; J. Heterocycl. Chem. 1994,31(1), 73-75; Hwu, J. R.; Wong, F. F.; Shiao, M.-J.; J. Org. Chem. 1992,57(19), 5254-5255; Shiao, M.-J.; Lai, L.-L.; Ku, W.-S.; Lin, P.-Y.; Hwu,J. R.; J. Org. Chem. 1993, 58(17), 4742-4744.

The introduction of an alkoxy or aryloxy substituent onto the azaindole(Step G, Scheme 31, R₂ is alkoxy or aryloxy) may be accomplished by thef procedures described in Klemm, L. H.; Zell, R.; J. Heterocycl. Chem.1968, 5, 773; Bradsher, C. K.; Brown, F. C.; Porter, H. K.; J. Am. Chem.Soc. 1954, 76, 2357; and Hodgson, H. H.; Foster, C. K.; J. Chem. Soc.1942, 581.

The introduction of a fluorine substituent onto the azaindole (Step G,Scheme 31) may be accomplished according to the procedures as describedin Sanchez, J. P.; Gogliotti, R. D.; J. Heterocycl. Chem. 1993, 30(4),855-859; Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G.; TetrahedronLett. 1993, 34(18), 2937-2940; and Sanchez, J. P.; Rogowski, J. W.; J.Heterocycl. Chem. 1987, 24, 215.

The introduction of a chlorine substituent onto the azaindole (Step G,Scheme 31) may be accomplished according to the procedures as describedin Ciurla, H.; Puszko, A.; Khim Geterotsikl Soedin 1996, 10, 1366-1371;Raveglia, L. F.; Giardinal, G. A. M.; Grugni, M.; Rigolio, R.; Farina,C.; J. Heterocycl. Chem. 1997, 34(2), 557-559; Matsumoto, J. I.;Miyamoto, T.; Minamida, A.; Mishimura, Y.; Egawa, H.; Mishimura, H.; J.Med. Chem. 1984, 27(3), 292; Lee, T.-C.; Salemnick, G.; J. Org. Chem.1975, 24, 3608.

The introduction of a bromine substituent onto the azaindole (Step G,Scheme 31) may be accomplished according to the procedures as describedin Raveglia, L. F.; Giardina, G. A. M.; Grugni, M.; Rigolio, R.; Farina,C.; J. Heterocycl. Chem. 1997, 34(2), 557-559; Talik, T.; Talik, Z.;Ban-Oganowska, H.; Synthesis 1974, 293; Abramovitch, R. A.; Saha, M.;Can. J. Chem. 1966, 44, 1765.

It is well known in the art that heterocycles may be prepared from analdehyde, carboxylic acid, carboxylic acid ester, carboxylic acid amide,carboxylic acid halide, or cyano moiety or attached to another carbonsubstituted by a bromide or other leaving group such as a triflate,mesylate, chloride, iodide, or phosponate. The methods for preparingsuch intermediates from intermediates typified by the carboxylic acidintermediate, 69, bromo intermediate, 76, or aldehyde intermediate, 70described above are known by a typical chemist practitioner. The methodsor types of heterocycles which may be constructed are described in thechemical literature. Some representative references for finding suchheterocycles and their construction are included in reference 55 through67 but should in no way be construed as limiting. However, examinationof these references shows that many versatile methods are available forsynthesizing diversely substituted heterocycles and it is apparent toone skilled in the art that these can be applied to prepare compounds ofFormula I. Chemists well versed in the art can now easily, quickly, androutinely find numerous reactions for preparing heterocycles, amides,oximes or other substituents from the above mentioned starting materialsby searching for reactions or preparations using a conventionalelectronic database such as Scifinder (American Chemical Society),Crossfire (Beilstein), Theilheimer, or Reaccs (MDS). The reactionconditions identified by such a search can then be employed using thesubstrates described in this application to produce all of the compoundsenvisioned and covered by this invention. In the case of amides,commercially available amines can be used in the synthesis.Alternatively, the above mentioned search programs can be used to locateliterature preparations of known amines or procedures to synthesize newamines. These procedures are then carried out by one with typical skillin the art to provide the compounds of Formula I for use as antiviralagents.

As shown below in Scheme 32, step a13, suitable substituted azaindoles,such as the bromoazaindole intermediate, 76, may undergo metal mediatedcouplings with aryl groups, heterocycles, or vinyl stannanes to providecompounds of Formula I wherein R₅ is aryl, heteroaryl, orheteroalicyclic for example. The bromoazaindole intermediates, 76 (orazaindole triflates or iodides) may undergo Stille-type coupling withheteroarylstannanes as shown in Scheme 32, step a13. Conditions for thisreaction are well known in the art and references 68-70 as well asreference 52 provide numerous conditions in addition to the specificexamples provided in Scheme 14 and in the specific embodiments. It canbe well recognized that an indole stannane could also couple to aheterocyclic or aryl halide or triflate to construct compounds ofFormula I. Suzuki coupling (reference 71) between the bromointermediate, 76, and a suitable boronate could also be employed andsome specific examples are contained in this application.

As shown in Scheme 34, step a14, aldehyde intermediates, 70, may be usedto generate numerous compounds of Formula I. The aldehyde group may be aprecursor for any of the substituents R₁ through R₅ but thetransormation for R₅ is depicted above for simplicity. The aldehydeintermediate 70, may be reacted to become incorporated into a ring as

described in the claims or be converted into an acyclic group. Thealdehyde, 70, may be reacted with a Tosmic based reagent to generateoxazoles (references 42 and 43 for example). The aldehyde, 70, may bereacted with a Tosmic reagent and than an amine to give imidazoles as inreference 72 or the aldehyde intermediate, 70, may be reacted withhydroxylamine to give an oxime which is a compound of Formula I asdescribed below. Oxidation of the oxime with NBS, t-butyl hypochlorite,or the other known reagents would provide the N-oxide which react withalkynes or 3 alkoxy vinyl esters to give isoxazoles of varyingsubstitution. Reaction of the aldehyde intermediate 70, with the knownreagent, 77 (reference 70) shown below under basic conditions wouldprovide 4-aminotrityl oxazoles.

Removal of the trityl group would provide 4-amino oxazoles which couldbe substitutued by acylation, reductive alkylation or alkylationreactions or heterocycle forming reactions. The trityl could be replacedwith an alternate protecting group such as a monomethoxy trityl, CBZ,benzyl, or appropriate silyl group if desired. Reference 73 demonstratesthe preparation of oxazoles containing a triflouoromethyl moiety and theconditions described therein demonstrates the synthesis of oxazoles withfluorinated methyl groups appended to them.

The aldehyde could also be reacted with a metal or Grignard (alkyl,aryl, or heteroaryl) to generate secondary alcohols. These would beefficacious or could be oxidized to the ketone with TPAP or MnO₂ or PCCfor example to provide ketones of Formula I which could be utilized fortreatment or reacted with metal reagents to give tertiary alcohols oralternatively converted to oximes by reaction with hydroxylaminehydrochlorides in ethanolic solvents. Alternatively the aldehyde couldbe converted to benzyl amines via reductive amination. An example ofoxazole formation via a Tosmic reagent is shown below in Scheme 35. Thesame reaction would work with aldehydes at other positions and also inthe 5 and 6 aza indole series.

Scheme 36 shows in step al5, a cyano intermediate, such as 62, whichcould be directly converted to compounds of Formula I via heterocycleformation or reaction with organometallic reagents.

Scheme 37 shows a method for acylation of a cyanoindole intermediate offormula 65 with oxalyl chloride which would give acid chloride, 79,which could then be coupled with the appropriate amine in the presenceof base to provide 80.

The nitrile intermediate, 80, could be converted to the tetrazole offormula 81, which could then be alkylated withtrimethylsilyldiazomethane to give the compound of formula 82 (Scheme38).

Tetrazole alkylation with alkyl halides would be carried out prior toazaindole acylation as shown in Scheme 39. Intermediate 65 could beconverted to tetrazole, 83, which could be alkylated to provide 84.Intermediate 84 could then be acylated and hydrolyzed to provide 85which could be subjected to amide formation conditions to provide 86.The group appended to the tetrazole may be quite diverse and stillexhibit impressive potency.

Scheme 40 shows that an oxadiazole such as, 88, may be prepared by theaddition of hydroxylamine to the nitrile, 80, followed by ring closureof intermediate 87 with phosgene. Alkylation of oxadiazole, 88, withtrimethylsilyldiazomethane would give the compound of formula 89.

A 7-cyanoindole, such as 80, could be efficiently converted to theimidate ester under conventional Pinner conditions using 1,4-dioxane asthe solvent. The imidate ester can be reacted with nitrogen, oxygen andsulfur nucleophiles to provide C7-substituted indoles, for example:imidazolines, benzimidazoles, azabenzimidazoles, oxazolines,oxadiazoles, thiazolines, triazoles, pyrimidines and amidines etc. Forexample the imidate may be reacted with acetyl hydrazide with heating ina nonparticipating solvent such as dioxane, THF, or benzene for example.(aqueous base or aqueous base in an alcoholic solvent may need to beadded to effect final dehydrative cyclization in some cases) to form amethyl triazine. Other hydrazines can be used. Triazines can also beinstalled via coupling of stannyl triazines with 4, 5, 6, or 7-bromo orchloro azaindoles. The examples give an example of the formation of manyof these heterocycles.

REFERENCES

-   (1) Das, B. P.; Boykin, D. W. J. Med. Chem. 1977, 20, 531.-   (2) Czarny, A.; Wilson, W. D.; Boykin, D. W. J. Heterocyclic Chem.    1996, 33, 1393.-   (3) Francesconi, I.; Wilson, W. D.; Tanious, F. A.; Hall, J. E.;    Bender, B. C.; Tidwell, R. R.; McCurdy, D.; Boykin, D. W. J. Med.    Chem. 1999, 42, 2260.

Scheme 41 shows addition of either hydroxylamine or hydroxylamine aceticacid to aldehyde intermediate 90 may give oximes of Formula 91.

An acid may be a precursor for substituents R₁ through R₅ when itoccupies the corresponding position such as R₅ as shown in Scheme 42.

An acid intermediate, such as 69, may be used as a versatile precursorto generate numerous substituted compounds. The acid could be convertedto hydrazonyl bromide and then a pyrazole via reference 74. One methodfor general heterocycle synthesis would be to convert the acid to analpha bromo ketone (ref 75) by conversion to the acid chloride usingstandard methods, reaction with diazomethane, and finally reaction withHBr. The alpha bromo ketone could be used to prepare many differentcompounds of Formula I as it can be converted to many heterocycles orother compounds of Formula I. Alpha amino ketones can be prepared bydisplacement of the bromide with amines. Alternatively, the alpha bromoketone could be used to prepare heterocycles not available directly fromthe aldeheyde or acid. For example, using the conditions of Hulton inreference 76 to react with the alpha bromo ketone would provideoxazoles. Reaction of the alpha bromoketone with urea via the methods ofreference 77 would provide 2-amino oxazoles. The alpha bromoketone couldalso be used to generate furans using beta keto esters (ref 78-80) orother methods, pyrroles (from beta dicarbonyls as in ref 81 or byHantsch methods (ref 82) thiazoles, isoxazoles and imidazoles (ref 83)example using literature procedures. Coupling of the aforementioned acidchloride with N-methyl-O-methyl hydroxyl amine would provide a “WeinrebAmide” which could be used to react with alkyl lithiums or Grignardreagents to generate ketones. Reaction of the Weinreb anion with adianion of a hydroxyl amine would generate isoxazoles (ref 84). Reactionwith an acetylenic lithium or other carbanion would generate alkynylindole ketones. Reaction of this alkynyl intermediate with diazomethaneor other diazo compounds would give pyrazoles (ref 85). Reaction withazide or hydroxyl amine would give heterocycles after elimination ofwater. Nitrile oxides would react with the alkynyl ketone to giveisoxazoles (ref 86). Reaction of the initial acid to provide an acidchloride using for example oxalyl chloride or thionyl chloride ortriphenyl phosphine/carbon tetrachloride provides a useful intermediateas noted above. Reaction of the acid chloride with an alpha estersubstituted isocyanide and base would give 2-substituted oxazoles (ref87). These could be converted to amines, alcohols, or halides usingstandard reductions or Hoffman/Curtius type rearrangements.

Scheme 43 describes alternate chemistry for installing the oxoacetylpiperazine moiety onto the 3 position of the azaindoles. Step A′″ inScheme 43 depicts reaction with formaldehyde and dimethylamine using theconditions in Frydman, B.; Despuy, M. E.; Rapoport, H.; J. Am. Chem.Soc. 1965, 87, 3530 will provide the dimethylamino compound shown.

Step B′″ shows displacement with potassium cyanide would provide thecyano derivative according to the method described in Miyashita, K.;Kondoh, K.; Tsuchiya, K.; Miyabe, H.; Imanishi, T.; Chem. Pharm. Bull.1997, 45(5), 932-935 or in Kawase, M.; Sinhababu, A. K.; Borchardt, R.T.; Chem. Pharm. Bull. 1990, 38(11), 2939-2946. The same transformationcould also be carried out using TMSCN and a tetrabutylammonium flouridesource as in Iwao, M.; Motoi, O.; Tetrahedron Lett. 1995, 36(33),5929-5932. Sodium cyanide could also be utilized.

Step C′″ of Scheme 43 depicts hydrolysis of the nitrile with sodiumhydroxide and methanol would provide the acid via the methods describedin Iwao, M.; Motoi, O.; Tetrahedron Lett. 1995, 36(33), 5929-5932 forexample. Other basic hydrolysis conditions using either NaOH or KOH asdescribed in Thesing, J.; et al.; Chem. Ber. 1955, 88, 1295 andGeissman, T. A.; Armen, A.; J. Am. Chem. Soc. 1952, 74, 3916. The use ofa nitrilase enzyme to achieve the same transformation is described byKlempier N, de Raadt A, Griengl H, Heinisch G, J. Heterocycl. Chem.,1992 29, 93, and may be applicable.

Step D′″ of Scheme 43 depicts an alpha hydroxylation which may beaccomplished by methods as described in Hanessian, S.; Wang, W.; Gai,Y.; Tetrahedron Lett. 1996, 37(42), 7477-7480; Robinson, R. A.; Clark,J. S.; Holmes, A. B.; J. Am. Chem. Soc. 1993, 115(22), 10400-10401(KN(TMS)₂ and then camphorsulfonyloxaziridine or another oxaziridine;and Davis, F. A.; Reddy, R. T.; Reddy, R. E.; J. Org. Chem. 1992,57(24), 6387-6389.

Step E′″ of Scheme 43 shows methods for the oxidation of the alphahydroxy ester to the ketone which may be accomplished according to themethods described in Mohand, S. A.; Levina, A.; Muzart, J.; Synth. Comm.1995, 25 (14), 2051-2059. A preferred method for step E′″ is that of Ma,Z.; Bobbitt, J. M.; J. Org. Chem. 1991, 56(21), 6110-6114 which utilizes4-(NH-Ac)-TEMPO in a solvent such as CH₂Cl₂ in the presence of paratoluenesulfonic acid. The method described in Corson, B. B.; Dodge, R.A.; Harris, S. A.; Hazen, R. K.; Org. Synth. 1941, I, 241 for theoxidation of the alpha hydroxy ester to the ketone uses KmnO₄ asoxidant. Other methods for the oxidation of the alpha hydroxy ester tothe ketone include those described in Hunaeus; Zincke; Ber. Dtsch Chem.Ges. 1877, 10, 1489; Acree; Am. Chem. 1913, 50, 391; and Claisen; Ber.Dtsch. Chem. Ges. 1877, 10, 846.

Step F′″ of Scheme 43 depicts the coupling reactions which may becarried out as described previously in the application and by apreferred method which is described in Li, H.; Jiang, X.; Ye, Y.-H.;Fan, C.; Romoff, T.; Goodman, M. Organic Lett., 1999, 1, 91-93 andemploys 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT);a new coupling reagent with remarkable resistance to racemization.

Scheme 44 depicts the preparation of Formula I compounds by couplingHWC(O)A to the acid as described in Step F′″ of Scheme 43, followed byhydroxylation as in Step D′″ of Scheme 43 and oxidation as described inStep E′″ of Scheme 43.

Scheme 45 depicts a method for the preparation which could be used toobtain amido compounds of Formula I. Step G′ represents ester hydrolysisfollowed by amide formation (Step H′ as described in Step F′″ of Scheme43). Step I′ of Scheme 45 depicts the preparation of the N-oxide whichcould be accomplished according to the procedures in Suzuki, H.; Iwata,C.; Sakurai, K.; Tokumoto, K.; Takahashi, H.; Hanada, M.; Yokoyama, Y.;Murakami, Y.; Tetrahedron 1997, 53(5), 1593-1606; Suzuki, H.; Yokoyama,Y.; Miyagi, C.; Murakami, Y.; Chem. Pharm. Bull. 1991, 39(8), 2170-2172;and Ohmato, T.; Koike, K.; Sakamoto, Y.; Chem. Pharm. Bull. 1981, 29,390. Cyanation of the N-oxide is shown in Step J′ of Scheme 45 which maybe accomplished according to Suzuki, H.; Iwata, C.; Sakurai, K.;Tokumoto, K.; Takahashi, H.; Hanada, M.; Yokoyama, Y.; Murakami, Y.;Tetrahedron 1997, 53(5), 1593-1606 and Suzuki, H.; Yokoyama, Y.; Miyagi,C.; Murakami, Y.; Chem. Pharm. Bull. 1991, 39(8), 2170-2172. Hydrolysisof the nitrile to the acid is depicted in Step K′ of Scheme 45 accordingto procedures such as Shiotani, S.; Tanigucchi, K.; J. Heterocycl. Chem.1996, 33(4), 1051-1056; Memoli, K. A.; Tetrahedron Lett. 1996, 37(21),3617-3618; Adolfsson, H.; Waernmark, K.; Moberg, C.; J. Org. Chem. 1994,59(8), 2004-2009; and El Hadri, A.; Leclerc, G.; J. Heterocycl. Chem.1993, 30(3), 631-635. Step L′ of Scheme 45 depicts a method which couldbe utilized for the preparation of amido compounds of Formula I from thecyano derivative which may be accomplished according to proceduresdescribed in Shiotani, S.; Taniguchi, K.; J. Heterocycl. Chem. 1997,34(2), 493-499; Boogaard, A. T.; Pandit, U. K.; Koomen, G.-J.;Tetrahedron 1994, 50(8), 2551-2560; Rivalle, C.; Bisagni, E.;Heterocycles 1994, 38(2), 391-397; and Macor, J. E.; Post, R.; Ryan, K.;J. Heterocycl. Chem. 1992, 29(6), 1465-1467. Step M′ of Scheme 45 showsa method which could be used for the preparation of amido compounds ofFormula I from the acid derivative which may be accomplished accordingto procedures described in Norman, M. H.; Navas, F. III; Thompson, J.B.; Rigdon, G. C.; J. Med. Chem. 1996, 39(24), 4692-4703; Hong, F.;Pang, Y.-P.; Cusack, B.; Richelson, E.; J. Chem. Soc., Perkin Trans 11997, 14, 2083-2088; Langry, K. C.; Org. Prep. Proced. Int. 1994, 26(4),429-438; Romero, D. L.; Morge, R. A.; Biles, C.; Berrios-Pena, N.; May,P. D.; Palmer, J. R.; Johnson, P. D.; Smith, H. W.; Busso, M.; Tan,C.-K.; Voorman, R. L.; Reusser, F.; Althaus, I. W.; Downey, K. M.; etal.; J. Med. Chem. 1994, 37(7), 999-1014 and Bhattacharjee, A.;Mukhopadhyay, R.; Bhattacharjya, A.; Indian J. Chem., Sect B 1994,33(7), 679-682.

Scheme 46 shows a method which could be used for the synthesis of anazaindole acetic acid derivative. Protection of the amine group could beeffected by treatment with di-tert-butyldicarbonate to introduce thet-Butoxycarbonyl (BOC) group. Introduction of the oxalate moiety maythen be accomplished as shown in Step A of Scheme 46 according to theprocedures described in Hewawasam, P.; Meanwell, N. A.; TetrahedronLett. 1994, 35(40), 7303-7306 (using t-Buli, or s-buli, THF); orStanetty, P.; Koller, H.; Mihovilovic, M.; J. Org. Chem. 1992, 57(25),6833-6837 (using t-Buli). The intermediate thus formed could then becyclized to form the azaindole as shown in Step B of Scheme 46 accordingto the procedures described in Fuerstner, A.; Ernst, A.; Krause, H.;Ptock, A.; Tetrahedron 1996, 52(21), 7329-7344 (using. TiCl3, Zn, DME);or Fuerstner, A.; Hupperts, A.; J. Am. Chem. Soc. 1995, 117(16),4468-4475 (using Zn, excess Tms-C1, TiCl3 (cat.), MeCN).

Scheme 47 describes an alternate synthesis which could be used toprepare azaindole acetic acid derivatives. Step C of Scheme 47 could beaccomplished by using the procedures described in Harden, F. A.; Quinn,R. J.; Scammells, P. J.; J. Med. Chem. 1991, 34(9), 2892-2898 [use of 1.NaNO₂, conc. HCl 2. SnCl₂, conc. HCl (cat.)]. Typically, 10 equivalentsof NaNO₂ and 1.0 equivalents of substrate reacted at 0° C. for 0.25 to 1h and to this reaction mixture was added 3.5 equivalents of SnCl₂.Alternatively, the procedure described in De Roos, K. B.; Salemink, C.A.; Recl. Trav. Chim. Pays-Bas 1971, 90, 1181 (use of NaNO₂, AcOH, H₂O)could be used. The intermediate thus formed could be further reacted andcyclized to provide azaindole acetic acid derivatives as shown in Step Dof Scheme 47 and according to the procedures described inAtkinson, C.M.; Mattocks, A. R.; J. Chem. Soc. 1957, 3722; Ain Khan, M.; Ferreira DaRocha, J.; Heterocycles 1978, 9, 1617; Fusco, R.; Sannicolo, F.;Tetrahedron 1980, 36, 161[use of HCl (conc)]; Abramovitch, R. A.;Spenser, I. D.; Adv. Heterocycl. Chem. 1964, 3, 79 (use of ZnCl₂,p-Cymene); and Clemo, G. R.; Holt, R. J. W.; J. Chem. Soc. 1953, 1313;(use of ZnCl₂, EtOH, Sealed tube).

Scheme 48 depicts another possible route to azaindole acetic acidderivatives. Step E of Scheme 48 could be carried out as shown oraccording to procedures such as those described in Yurovskaya, M. A.;Khamlova, I. G.; Nesterov, V. N.; Shishkin, O. V.; Struchkov, T.; KhimGeterotsikl Soedin 1995, 11, 1543-1550; Grzegozek, M.; Wozniak, M.;Baranski, A.; Van Der Plas, H. C.; J. Heterocycl. Chem. 1991, 28(4),1075-1077 (use of NaOH, DMSO); Lawrence, N. J.; Liddle, J.; Jackson, D.A.; Tetrahedron Lett. 1995, 36(46), 8477-8480 (use of NaH, DMSO);Haglund, O.; Nilsson, M.; Synthesis 1994, 3, 242-244; (use of 2.5 equiv.CuCl, 3.5 equiv. TBu-OK, DME, Py); Makosza, M.; Sienkiewicz, K.;Wojciechowski, K.; Synthesis 1990, 9, 850-852; (use of KO-tBu, DMF);Makosza, M.; Nizamov, S.; Org. Prep. Proceed. Int. 1997, 29(6), 707-710;(use of tBu-OK, THF). Step F of Scheme 48 shows the cyclization reactionwhich could provide the azaindole acetic acid derivatives. This reactioncould be accomplished according to procedures such as those described inFrydman, B.; Baldain, G.; Repetto, J. C.; J. Org. Chem. 1973, 38, 1824(use of H₂, Pd-C, EtOH); Bistryakova, I. D.; Smirnova, N. M.; Safonova,T. S.; Khim Geterotsikl Soedin 1993, 6, 800-803 (use of H_(z),Pd-C(cat.), MeOH); Taga, M.; Ohtsuka, H.; Inoue, I.; Kawaguchi, T.;Nomura, S.; Yamada, K.; Date, T.; Hiramatsu, H.; Sato, Y.; Heterocycles1996, 42(1), 251-263 (use of SnCl₂, HCl, Et₂O); Arcari, M.; Aveta, R.;Brandt, A.; Cecchetelli, L.; Corsi, G. B.; Dirella, M.; Gazz. Chim.Ital. 1991, 121(11), 499-504 [use of Na₂S₂O₆, THF/EtOH/H₂O (2:2:0];Moody, C. J.; Rahimtoola, K. F.; J. Chem. Soc., Perkin Trans 1 1990, 673(use of TiCl₃, NH₄Oac, acetone, H₂O).

Scheme 49 provides another route to azaindole intermediates which couldthen be further elaborated to provide compounds of Formula I, such asthe amido derivatives shown. Steps G″. and H″ of Scheme 49 may becarried out according to the procedures described in Takahashi, K.;Shibasaki, K.; Ogura, K.; Lida, H.; Chem. Lett. 1983, 859; and Itoh, N.;Chem. Pharm. Bull. 1962, 10, 55. Elaboration of the intermediate to theamido compound of Formula I could be accomplished as previouslydescribed for Steps I′-M′ of Scheme 45.

Scheme 50 shows the preparation of azaindole oxalic acid derivatives.The starting materials in Scheme 50 may be prepared according toTetrahedron Lett. 1995, 36, 2389-2392. Steps A′, B′, C′, and D′ ofScheme 50 may be carried out according to procedures described in Jones,R. A.; Pastor, J.; Siro, J.; Voro, T. N.; Tetrahedron 1997, 53(2),479-486; and Singh, S. K.; Dekhane, M.; Le Hyaric, M.; Potier, P.; Dodd,R. H.; Heterocycles 1997, 44(1), 379-391. Step E′ of Scheme 50 could becarried out according to the procedures described in Suzuki, H.; Iwata,C.; Sakurai, K.; Tokumoto, K.; Takahashi, H.; Hanada, M.; Yokoyama, Y.;Murakami, Y.; Tetrahedron 1997, 53(5), 1593-1606; Suzuki, H.; Yokoyama,Y.; Miyagi, C.; Murakami, Y.; Chem. Pharm. Bull. 1991, 39(8), 2170-2172;Hagen, T. J.; Narayanan, K.; Names, J.; Cook, J. M.; J. Org. Chem. 1989,54, 2170; Murakami, Y.; Yokoyama, Y.; Watanabe, T.; Aoki, C.; et al.;Heterocycles 1987, 26, 875; and Hagen, T. J.; Cook, J. M.; TetrahedronLett. 1988, 29(20), 2421. Step F′ of Scheme 50 shows the conversion ofthe phenol to a fluoro, chloro or bromo derivative. Conversion of thephenol to the fluoro derivative could be carried out according toprocedures described in Christe, K. O.; Pavlath, A. E.; J. Org. Chem.1965, 30, 3170; Murakami, Y.; Aoyama, Y.; Nakanishi, S.; Chem. Lett.1976, 857; Christe, K. O.; Pavlath, A. E.; J. Org. Chem. 1965, 30, 4104;and Christe, K. O.; Pavlath, A. E.; J. Org. Chem. 1966, 31, 559.Conversion of the phenol to the chloro derivative could be carried outaccording to procedures described in Wright, S. W.; Org. Prep. Proc.Int. 1997, 29(1), 128-131; Hartmann, H.; Schulze, M.; Guenther, R.; DyesPigm 1991, 16(2), 119-136; Bay, E.; Bak, D. A.; Timony, P. E.;Leone-Bay, A.; J. Org. Chem. 1990, 55, 3415; Hoffmann, H.; et al.; Chem.Ber. 1962, 95, 523; and Vanallan, J. A.; Reynolds, G. A.; J. Org. Chem.1963, 28, 1022. Conversion of the phenol to the bromo derivative may becarried out according to procedures described in Katritzky, A. R.; Li,J.; Stevens, C. V.; Ager, D. J.; Org. Prep. Proc. Int. 1994, 26(4),439-444; Judice, J. K.; Keipert, S. J.; Cram, D. J.; J. Chem. Soc.,Chem. Commun. 1993, 17, 1323-1325; Schaeffer, J. P.; Higgins, J.; J.Org. Chem. 1967, 32, 1607; Wiley, G. A.; Hershkowitz, R. L.; Rein, R.M.; Chung, B. C.; J. Am. Chem. Soc. 1964, 86, 964; and Tayaka, H.;Akutagawa, S.; Noyori, R.; Org. Syn. 1988, 67, 20.

Scheme 51 describes methods for the preparation of azaindole acetic acidderivatives by the same methods employed for the preparation ofazaindole oxalic acid derivatives as shown and described in Scheme 50above. The starting material employed in Scheme 51 could be preparedaccording to J. Org. Chem. 1999, 64, 7788-7801. Steps A″, B″, C″, D″,and E″ of Scheme 51 could be carried out in the same fashion aspreviously described for Steps A′, B′, C′, D′, and E′ of Scheme 50.

The remaining schemes provide additional background, examples, andconditions for carrying out this invention. Specific methods forpreparing W and modifying A are presented. As shown in Scheme 52, theazaindoles may be treated with oxalyl chloride in either THF or ether toafford the desired glyoxyl chlorides according to literature procedures(Lingens, F.; Lange, J. Justus Liebigs Ann. Chem. 1970, 738, 46-53). Theintermediate glyoxyl chlorides may be coupled with benzoyl piperazines(Desai, M.; Watthey, J. W. Org. Prep. Proc. Int. 1976, 8, 85-86) underbasic conditions to afford compounds of Formula I directly.

Alternatively, Scheme 52 treatment of the azaindole-3-glyoxyl chloride,(Scheme 52) with tert-butyl 1-piperazinecarboxylate affords thepiperazine coupled product. It is apparent to one skilled in the artthat use of an alternative Boc protected piperazine which aresynthesized as shown below would provide compounds of formula I withalternative groups of formula W. As discussed earlier, other amineprotecting groups which do not require acidic deprotection conditionscould be utilized if desired. Deprotection of the Boc group is effectedwith 20% TFA/CH₂Cl₂ to yield the free piperazine. This product is thencoupled with carboxylic acid in the presence of polymer supported1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (P-EDC) to afford productsof Formula I. This sequence provides a general method for synthesizingcompounds of varied A in formula I.

An example for preparing compounds of Formula I which possesssubstituents in A (or other parts of the molecule) which might interferewith the standard reaction schemes reactions is shown in Scheme 53. Thepiperazine derivative (Scheme 53) was treated with Boc-protectedaminobenzoic acid in the presence of EDC to afford the piperazinediamide. A portion of the resulting product was separated and subjectedto TFA in order to remove the Boc group, thus yielding aminoderivatives.

Similarly, substituents which possess a reactive alcohol can beincorporated as below. The piperazine derivative (Scheme 54) was treatedwith acetoxybenzoic acid in the presence of EDC to afford the piperazinediamide derivative. A portion of the resulting product was separated andsubjected to LiOH hydrolysis in order to remove the acetate group, thusyielding hydroxy derivatives.

Examples containing substituted piperazines are prepared using thegeneral procedures outlined in Schemes 55-38. Substituted piperazinesare either commercially available from Aldrich, Co. or preparedaccording to literature procedures (Behun et al, Ref 88(a), Scheme 31,eq. 01). Hydrogenation of alkyl substituted pyrazines under 40 to 50 psipressure in EtOH afforded substituted piperazines. When the substituentwas an ester or amide, the pyrazine systems could be partially reducedto the tetrahydropyrazine (Rossen et al, Ref 88(b), Scheme 55, eq. 02).The carbonyl substituted piperazines could be obtained under the sameconditions described above by using commercially available dibenzylpiperazines (Scheme 55, eq. 03).

2-Trifluoromethylpiperazine (Jenneskens et al., Ref 88c) was preparedthrough a four step route (Scheme 56). Using Lewis acid TiCl₄,N,N′-dibenzylethylenediamine reacted with trifluoropyruvates to affordthe hemiacetal, which was reduced at room temperature by Et₃SiH in TFAto afford the lactam. LiAlH₄ treatment then reduced the lactam to1,4-dibenzyl-2-trifluoromethylpiperazine. Finally, hydrogenation of thedibenzyl-2-trifluoromethylpiperazine in HOAc gave the desired product,2-trifluoromethylpiperazine.

Mono-benzoylation of symmetric substituted piperazines could be achievedby using one of the following procedures (Scheme 57). (a) Treatment of asolution of piperazine in acetic acid with acetyl chloride afforded thedesired mon-benzoylated piperazine (Desai et al. Ref 27, Scheme 57, eq.04). (b) Symmetric piperazines were treated with 2 equivalents ofn-butyllithium, followed by the addition of benzoyl chloride at roomtemperature (Wang et al, Ref 89, Scheme 57, eq. 05).

Mono-benzoylation of unsymmetric substituted piperazines could beachieved by using one of the following procedures (Scheme 57), in whichall the methods were exemplified by mono-alkyl substituted piperazines.(a) Unsymmetric piperazines were treated with 2 equivalents ofn-butyllithium, followed by the addition of benzoyl chloride at roomtemperature to afford a mixture of two regioisomers, which could beseparated by chromatography (Wang et al, Ref 89 and 90(b), Scheme 58 eq.06); (b) Benzoic acid was converted to its pentafluorophenyl ester, andthen further reaction with 2-alkylpiperazine to provide themono-benzoylpiperazines with the benzoyl group at the less hinderednitrogen (Adamczyk et al, Ref 90(a), Scheme 58, eq. 07); (c) A mixtureof piperazine and methyl benzoate was treated with dialkylaluminumchloride in methylene chloride for 2-4 days to yield themono-benzoylpiperazine with the benzoyl group at the less hinderednitrogen (Scheme 58 eq. 08); (d) Unsymmetric piperazines were treatedwith 2 equivalents of n-butyllithium, followed by subsequent addition oftriethylsilyl chloride and benzoyl chloride in THF at room temperatureto afford mono-benzoylpiperazines with the benzoyl group at the morehindered nitrogen (Wang et al, Ref 90(b), Scheme 58, eq. 09). When thesubstituent at position 2 was a ester or amide, the mono-benzoylationwith benzoyl chloride occurred at the less hindered nitrogen of thepiperazine with triethylamine as base in THF (Scheme 58, eq. 10).

In the case of tetrahydropyrazines (Scheme 59, eq. 11),mono-benzoylation occurred at the more hindered nitrogen under the sameconditions as those in equation 10 of Scheme 58, in the well precedentedmanner. (Rossen et al, Ref 88(b)).

Furthermore, the ester group can be selectively reduced by NaBH₄ in thepresence of the benzamide (Masuzawa et al, Ref 91), which is shown inScheme 60.

The ester groups on either the piperazine linkers or on the azaindolenucleus could be hydrolyzed to the corresponding acid under basicconditions such as K₂CO₃ (Scheme 61, eq. 13) or NaOMe (Scheme 61, eq.14) as bases in MeOH and water.

Reaction of an azaindole glyoxyl chloride with substituted benzoylpiperazines or tetrahydropyrazines in CH₂Cl₂ using I-Pr₂Net as baseafforded the coupled products as shown in Scheme 62.

In the case of coupling reactions using3-hydroxylmethyl-benzoylpiperazine, the hydroxyl group was temporarilyprotected as its TMS ether with BSTFA(N,O-bistrimethylsilyl)trifluoroacetamide) (Furber et al, Ref 92). Theunprotected nitrogen atom can then be reacted with glyoxyl chlorides toform the desired diamides. During workup, the TMS masking group wasremoved to give free hydroxylmethylpiperazine diamides as shown inScheme 63.

Piperazine intermediates were prepared using standard chemistry as shownin Scheme 64.

Scheme 65 depicts some more specific methodology for preparing5-azindoles for use in prpeartion of the claimed compounds. Somereductive cyclizations conditions include Fe in acetic acid, Tin IIchloride in aq HCl, or Zinc powder in acetic acid. Hydrogenationcondititons or other conditions used in LeimGruber-Batch indolesynthesis sequences can also be employed.

Tautomers of nitrogen containing heterocycles are covered by this patentapplication. For example, a hydroxy pyrazine is also known to representits corresponding tautomer as well as shown in Scheme 66.

Scheme 67-74 provides some nonlimiting methodology for the preparationof substituted pyrazines which can be incorporated into substituents ofcompounds of claim 1, particularly as part of R⁴. It should be notedthat the nomenclature in these schemes does not coincide with that ofthe claims but rather shows examples of methods which can be used toprepare pieces which make up the compounds of the claims. Thus R₁ and R₂in these schemes does not refer to the R1 and R2 in the claims but forexample refers to chemically compatible groups which might be envisionedby chemists skilled in the art and which can be utilized to preparecompounds of the claims.

Throughout the chemistry discussion, chemical transformations which arewell known in the art have been discussed. The average practioner in theart knows these transformations well and a comprehensive list of usefulconditions for nearly all the transformations is available to organicchemists and this list is contained in reference 52 authored by Larockand is incorporated in its entirety for the synthesis of compounds ofFormula I.

Schemes 75-78 provide more specific examples of the general synthesisdescribed in Scheme 1. The examples describe the synthesis of compoundsof the invention in which the piperazine of group W contains asubstituent on the ring at a position next to the nitrogen whichcomprises part of the amide attached to group A. While othersubstitution patterns are important aspects of the invention, we havefound that compounds with a single group adjacent to the amide attachedto group A may have metabolic stability advantages in humans and yetretain exceptional antiviral properties. The specific substitutedpiperazines described in Schemes 75-78 may be prepared as described inreference 90(b) or as described for intermediates 17a-d in theexperimental section. In schemes 75 and 76 the most preferred groups forR₉ and R₁₁ are C1-C6 alkyl groups. As shown in schemes 77 and 78 themost preferred groups are methyl. As shown in schemes 75-78, thecompounds may be single isomers or enantiomers or may be used as aracemic mixture or mixture of isomers. Preferred groups A as shown inthe schemes 75-78 are the same as those described for the invention.Most preferred groups A are 2-pyridyl or phenyl. In Schemes 75 and 77,the most preferred groups for R₂ are methoxy, halogen, or hydrogen. Inschemes 75-76 the most preferred group for R1 and R3 is hydrogen. Inscheme 76 the most preferred group for R2 is hydrogen. In schemes 75-78,the most preferred groups for R4 are phenyl, substituted phenyl,heteroaryl, substituted heteroaryl, —C(O)NH2, —C(O)NHMe, orC(O)heteroaryl. Most preferred substituents on the substituted aryl orheteroaryl are methyl, amino, halogen, C(O)NHMe, COOH, COOMe, COOEt, orbenzyl but this list should not be construed to be rate limiting as theR4 position is extremely tolerant of broad substitution. Particulargroups at R4 of definite importance are triazole, oxadiazole, oxazole,pyrazole, pyrazine, pyrimidine, tetrazole, and phenyl but should not beconstrued as limiting.

Schemes 79 provides examples and typical conditions for formingintermediates 2 which contain an oxadiazole or substituted oxadiazole.These intermediates can be converted to compounds of claim 1 via thestandard methodology described in Scheme 1 and the rest of theapplication. An alternate sequence is shown in Scheme 79a which utilizescyano substituted intermediates 5 to generate the oxadiazoles of claim1. Specific examples are given in the experimental section. Otheroxadiazole isomers may be prepared via standard literature methodology.

Scheme 80 is a preferred method for making compounds of Formula I and Iawhere R² is fluoro. This is exemplified specifically in the preparationof compound Example 216. The synthesis of2-hydroxy-3-nitro-5-fluoropyridine 5-80 as shown was carried outgenerally via the methods of A. Marfat and R. P. Robinson U.S. Pat. No.5,811,432 (column 25, example 5) and Nesnow and Heidleberger (J.Heterocyclic Chem. 1973, 10, pg 779) except that a number of proceduralenhancements were incorporated as noted in the description of each step.2-Hydroxy 5-fluoropyridine 4-80 is also commercially available. Theformation of diazonium tetrafluoroborate salt 2-80 from5-amino-2-methoxy pyridine 1-80 proceeded in essentially quantitativeyield and was isolated via filtration. The Schiemann reaction providedpoor yields of the desired 2-methoxy-fluoropyridine using the literatureconditions due mainly to significant contamination with 3-fluoro1-(N)-methyl pyridone and other byproducts. However, adoption of aprocedure similar to that described in Sanchez, J. P.; Rogowski, J. W.;J Heterocycl Chem 1987, 24, 215 for a related compound provided veryhigh yields of essentially clean but volatile 2-methoxy-5-fluoropyridine 3-80 as a solution in toluene. In the interest of expediency,demethylation was achieved on large scale using aqueous HCl in pressurebottles at 140° C. for 1 hr. Prior to heating, the toluene solution wasstirred with the aq HCl and then the toluene was removed by decantation.The literature method for carrying out this step using HBr at 100° C.was also successful on small scale and had the advantage of avoiding theuse of pressure bottles. Nitration of 4-80 as described by Marfatprovided lower than expected yields so the procedure was modifiedslightly, using guidance from A. G. Burton, P. J. Hallis, and A. R.Katritzky (Tetrahedron Letters 1971, 24, 2211-2212) on the control ofthe regiochemistry of nitration of pyridones via modulation of theacidity of the medium. The chemical yields of 2-hydroxy-3-nitro-5-fluoropyridine 5-80 were significantly improved using the procedure describedin the experimental section. Occasionally the product failed toprecipitate during workup and then considerable efforts were necessaryto isolate this highly water soluble compound from the aqueous layer.Using neat excess POBr₃, compound 5-80 was converted to2-bromo-3-nitro-5-fluoro pyridine 6 which could be used without furtherpurification in the subsequent azaindole forming reaction. Addition ofthe pyridine 6 to excess vinyl magnesium bromide in THF at lowtemperature afforded the desired 4-fluoro-7-bromo-6-azaindol (precursor5j) in yields of up to 35% following acidic work up and isolation viacrystallization. A disadvantage of this method is the workup isdifficult due to the large amounts of salts formed as co-products in thereaction and the low conversion to albeit clean product. The reaction isalso exothermic and thus would require care on larger scales. Despitethe moderate yields, as mentioned above the reaction proceeds cleanlyand provides pure product precursor 5j without chromatography so it isanticipated that more detailed studies of this chemistry could result inyield enhancements. A selective copper/potassium carbonate mediateddisplacement of the 7-bromo group by commercially available1,2,3-triazole provided an approximately 1:1 mixture of triazoles fromwhich the desired 7-80 was isolated via chromatography in 25-35% yields.Copper-bronze rather than copper powder can also be used to carry outsimilar transformations. This reaction must not be allowed to overheatsince concomitant displacement of the fluorine is possible and has beenobserved. Acylation occurred most efficiently under conditions thatutilized excess acidic imidazolium chloro aluminate ionic liquid toprovide highly activated glyoxylating reagent (K. S. Yeung et al.Tetrahedron Lett. 2002, 43, 5793). The acylation of 7-80 usually doesnot proceed to completion and typically results in about 75% conversionas measured by LC/MS. An advantage to these conditions is that thetypical next step, ester hydrolysis, proceeded in situ to provide thedesired acid 8-80 which was isolated directly by precipitation duringworkup. Coupling of the piperazine benzamide was found to be cleaner andproduced higher yields of the compound of Example 216 using the depictedHATU based coupling than with other standard coupling reagents such asEDC or DEPBT.

Chemistry General:

Additional preparations of starting materials and precursors arecontained in Wang et. al. U.S. Ser. No. 09/912,710 filed Jul. 25, 2001(which is a continuation-in-part of U.S. Ser. No. 09/765,189 filed Jan.18, 2001, abandoned, corresponding to PCT WO 01/62255) which isincorporated by reference.

Chemistry

All Liquid Chromatography (LC) data were recorded on a Shimadzu LC-10ASliquid chromatograph using a SPD-10AV UV-Vis detector with MassSpectrometry (MS) data determined using a Micromass Platform for LC inelectrospray mode.

LC/MS Method (i.e., compound identification)Column A: YMC ODS-A S7 3.0×50 mm columnColumn B: PHX-LUNA C18 4.6×30 mm columnColumn C: XTERRA ms C18 4.6×30 mm columnColumn D: YMC ODS-A C18 4.6×30 mm columnColumn E: YMC ODS-A C18 4.6×33 mm columnColumn P YMC C18 S5 4.6×50 mm columnColumn G: XTERRA C18 S7 3.0×50 mm columnColumn H: YMC C18 S5 4.6×33 mm columnColumn P YMC ODS-A C18 S7 3.0×50 mm columnColumn J: XTERRA C-18 S5 4.6×50 mm columnColumn K: YMC ODS-A C18 4.6×33 mm columnColumn L: Xterra MS C18 5 uM 4.6×30 mm columnColumn M: YMC ODS-A C18 S3 4.6×33 mm columnStandard LC Run Conditions (used unless otherwise noted):

-   Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B

Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1%TFA; and R_(t) in min.

Gradient time: 2 minutesHold time 1 minuteFlow rate: 5 mL/min

Detector Wavelength: 220 nm Solvent A: 10% MeOH/90% H₂O/0.1%Trifluoroacetic Acid Solvent B: 10% H₂O/90% MeOH/0.1% TrifluoroaceticAcid Alternate LC Run Conditions B:

-   Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B

Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1%TFA; and R_(t) in min.

Gradient time: 4 minutesHold time 1 minuteFlow rate: 4 mL/min

Detector Wavelength: 220 nm Solvent A: 10% MeOH/90% H₂O/0.1%Trifluoroacetic Acid Solvent B: 10% H₂O/90% MeOH/0.1% TrifluoroaceticAcid

Compounds purified by preparative HPLC were diluted in MeOH (1.2 mL) andpurified using the following methods on a Shimadzu LC-10A automatedpreparative HPLC system or on a Shimadzu LC-8A automated preparativeHPLC system with detector (SPD-10AV UV-VIS) wavelength and solventsystems (A and B) the same as above.

Preparative HPLC Method (i.e., Compound Purification)

Purification Method: Initial gradient (40% B, 60% A) ramp to finalgradient (100% B, 0% A) over 20 minutes, hold for 3 minutes (100% B, 0%A)

Solvent A: 10% MeOH/90% H₂O/0.1% Trifluoroacetic Acid Solvent B: 10%H₂O/90% MeOH/0.1% Trifluoroacetic Acid

Column: YMC C18 S5 20×100 mm column

Detector Wavelength: 220 nm Typical Procedures and Characterization ofSelected Examples: Preparation of Precursors: Precursor 1

4-Methoxyphenylboronic acid (24.54 g), 4-chloro-3-nitropyridinehydrochloride (26.24 g), Pd(Ph₃P)₄ (4 g) and K₂CO₃ (111 g) were combinedin DME (500 mL). The reaction was heated to reflux for 10 hours. Afterthe mixture cooled down to room temperature, it was poured intosaturated aqueous NH₄OAc (500 mL) solution. The aqueous phase wasextracted with EtOAc (3×200 mL). The combined extract was concentratedto give a residue which was purified using silica gel chromatography(10% to 30% EtOAc/PE) to afford 10.6 g of Precursor1,3-Nitro-4-(4-methoxyphenyl)pyridine. MS m/z: (M+H)⁺ calcd forC₁₂H₁₁N₂O₃: 231.08. found 231.02. HPLC retention time: 1.07 minutes(column B).

Precursor 1a

Alternate route to 5-azaindoles:

2-methoxy-5-bromo pyridine can be purchased from Aldrich (or others) orprepared. Oxidation with 1.1 eq of MCPBA in dichloromethane (20 ml per10 6 mmol bromide) in the presence of anhydrous MgSO4 (0.4 g per mLdichloromethane) with stirring from 0° to ambient temperature forapproximately 14 h provided the N-oxide after workup and flashchromatographic purification over silica gel using a 5% Etoac/Hexanegradient of increasing EtOAc. The N-oxide (1.6 g) was dissolved in 10 mL98% sulfuric acid and cooled to 0°. 10 mL of 69% nitric acid was addedand then allowed to warm to ambient temp with stirring. The reaction wasthen heated and stirred at 80° C. for 14 h and then poured over ice,extracted with dichloromethane, washed with water, and concentrated togive a yellow solid which was purified by flash chromatography overSilica gel using 1:1 EtOAc/hexane and then a gradient to provide ayellow crystalline solid:). ¹H NMR (CDCl3) δ 8.50 (s, 1H), 7.59 (s, 1H),4.12 (3H, s). LC MS showed desired M+H. The N-oxide was reduced bydissolving the startingmaterial in dichloromethane (0.147M substrate)and cooling to 0°. A solution of 1.2 eq PCl₃ (0.44M) in dicloromethanewas added slowly to keep the reaction at 0°. Warm to ambient temp andstir for 72 h. Aqueous workup and concentration provided a yellow solidwhich could be used in subsequent reactions or purified bychromatography. Note: a similar sequence could be used with2-methoxy-5-chloro-pyridine as starting material.

Precursor 2a

Typical Procedure for Preparing Azaindole from Nitropyridine:

Preparation of 7-chloro-6-azaindole, Precursor 2a, is an example of StepA of Scheme 1. 2-chloro-3-nitropyridine (5.0 g, 31.5 mmol) was dissolvedin dry THF (200 mL). After the solution was cooled to −78° C., vinylmagnesium bromide (1.0M in THF, 100 mL) was added dropwise. The reactiontemperature was maintained at −78° C. for 1 h, and then at −20° C. foranother 12 h before it was quenched by addition of 20% NH₄Cl aqueoussolution (150 mL). The aqueous phase was extracted with EtOAc (3×150mL). The combined organic layer was dried over MgSO₄, filtered and thefiltrate was concentrated in vacuo to give a residue which was purifiedby silica gel column chromatography (EtOAc/Hexane, 1/10) to afford 1.5 g(31%) of 7-chloro-6-azaindole, Precursor 2a. ¹H NMR (500 MHz, CD₃OD) δ7.84 (d, 1H, J=10.7 Hz), 7.55 (dd, 1H, J=10.9, 5.45 Hz), 6.62 (d, 1H,J=5.54 Hz), 4.89 (s, 1H). MS m/z: (M+H)⁺ calcd for C₇H₆ClN₂: 153.02.found 152.93. HPLC retention time: 0.43 minutes (column A).

Precursor 2b

Precursor 2b, 7-(4-Methoxyphenyl)-4-azaindole, was prepared by the samemethod as Precursor 2a starting from3-Nitro-4-(4-methoxyphenyl)pyridine, Precursor 1. MS m/z: (M+H)⁺ calcdfor C₁₄H₁₃N₂O: 225.10. found 225.02. HPLC retention time: 1.39 minutes(column B).

Precursor 2c

Precursor 2c, 4-bromo-7-chloro-6-azaindole, was prepared by the samemethod as Precursor 2a, starting from 2-Chloro-3-nitro-5-bromo-pyridine(available from Aldrich, Co.). MS m/z: (M+H)⁺ calcd for C₇H₅BrClN₂:230.93. found 231.15. HPLC retention time: 1.62 minutes (column B).

Precursor 2d

Precursor 2d, 4-fluoro-7-chloro-6-azaindole (above), was preparedaccording to the following scheme:

It should be noted that 2-chloro-5-fluoro-3-nitro pyridine, zz3′, may beprepared by the method in example 5B of the reference Marfat, A.; andRobinson, R. P.; “Azaoxindole Derivatives” U.S. Pat. No. 5,811,432 1998.The preparation below provides some details which enhance the yields ofthis route.

In Step A, compound zz1′ (1.2 g, 0.01 mol) was dissolved in sulfuricacid (2.7 mL) at room temperature. Premixed fuming nitric acid (1 mL)and sulfuric acid was added dropwise at 5-10° C. to the solution ofcompound zz1′. The reaction mixture was then heated at 85° C. for 1hour, then was cooled to room temperature and poured into ice (20 g).The yellow solid precipitate was collected by filtration, washed withwater and air dried to provide 1.01 g of compound zz2′.

In Step B, compound zz2′ (500 mg, 3.16 mmol) was dissolved inphosphorous oxychloride (1.7 mL, 18.9 mmol) and dimethoxyethane at roomtemperature. The reaction was heated to 110° C. for 5 hours. The excessphosphorous oxychloride was then removed by concentrating the reactionmixture in vacuo. The residue was chromatographed on silica gel, elutedwith chloroform (100%) to afford 176 mg of product zz3′.

In Step C, compound zz3′ (140 mg, 0.79 mmol) was dissolved in THF (5 mL)and cooled to −78° C. under a nitrogen atmosphere. To this solution wasadded dropwise a solution of vinyl magnesium bromide (1.2 mmol, 1.0 M indiethyl ether, 1.2 mL). The reaction mixture was then kept at −20° C.for 15 hours. The reaction mixture was then quenched with saturatedammonium chloride, and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over magnesium sulfate,filtered, and the filtrate was concentrated in vacuo. The residue waschromatographed on silica to provide 130 mg of precursor 2d ¹H NMR (500MHz, CD₃OD) δ 7.78 (s, 1H), 7.60 (d, 1H, J=3.0 Hz), 6.71 (d, 1H, J=3.05Hz). MS m/z: (M+H)⁺ calcd for C₇H₅ClFN₂: 171.10. found 171.00. HPLCretention time: 1.22 minutes (column A).

Precursor 2d, 4-fluoro-7-chloro-6-azaindole, was prepared by the samemethod as Precursor 2a, starting from 2-Chloro-3-nitro-5-fluoro-pyridinewhich was prepared according to the procedure above. Experimentaldetails for this preparation are contained in Wang et. al. PCT WO01/62255. ¹H NMR (500 MHz, CD₃OD) δ 7.78 (s, 1H), 7.60 (d, 1H, J=3.0Hz), 6.71 (d, 1H, J=3.05 Hz). MS m/z: (M+H)⁺ calcd for C₇H₅ClFN₂:171.10. found 171.00. HPLC retention time: 1.22 minutes (column A).

Precursor 2e

Precursor 2e was prepared by either Method A or Method B, below:

Method A: A mixture of 4-bromo-7-chloro-6-azaindole (1 g), CuI (0.65 g)and NaOMe (4 mL, 25% in methanol) in MeOH (16 mL) was heated at 110-120°C. for 16 hours in a sealed tube. After cooling to room temperature, thereaction mixture was neutralized with 1N HCl to pH 7. The aqueoussolution was extracted with EtOAc (3×30 mL). Then the combined organiclayer was dried over MgSO₄, filtered and the filtrate was concentratedin vacuo to afford a residue, which was purified by using silica gelchromotography to give 0.3 g of 4-methoxy-7-chloro-6-azaindole,Precursor 2e. MS m/z: (M+H)⁺ calcd for C₈H₈ClN₂O: 183.03. found 183.09.HPLC retention time: 1.02 minutes (column B).

Method B: A mixture of 4-bromo-7-chloro-6-azaindole (6 g), CuBr (3.7 g)and NaOMe (30 mL, 5% in MeOH) was heated at 110° C. for 24 hours in asealed tube. After cooling to room temperature, the reaction mixture wasadded to saturated aqueous NH₄Cl. The resulting aqueous solution wasextracted with EtOAc (3×30 mL). The combined organic layer was driedover MgSO₄, filtered and the filtrate was concentrated in vacuo toafford a residue, which was purified by using silica gel chromotographyto give 1.8 g of 4-methoxy-7-chloro-6-azaindole, Precursor 2e.

Precursor 2f

Precursor 2f, 7-bromo-6-azaindole was prepared by the same method asPrecursor 2a, starting from 2-Bromo-3-nitro-pyridine (available fromAldrich, Co.). MS m/z: (M+H)⁺ calcd for C₇H₆BrN₂: 197.97. found 197.01.HPLC retention time: 0.50 minutes (column A).

Precursor 2g

Precursor 2g, 7-chloro-4-azaindole was prepared by the same method asPrecursor 2a, starting from 4-Chloro-3-nitro-pyridine (HCl salt,available from Austin Chemical Company, Inc.). MS m/z: (M+H)⁺ calcd forC₇H₆ClN₂: 153.02. found 152.90. HPLC retention time: 0.45 minutes(column A).

Precursor 2h

Precursor 2h, 5-chloro-7-methyl-4-azaindole was prepared by the samemethod as Precursor 2a, starting from 2-Chloro-4-methyl-5-nitro-pyridine(available from Aldrich, Co.). MS m/z: (M+H)⁺ calcd for C₈H₈ClN₂:167.04. found 166.99. HPLC retention time: 1.22 minutes (column B).

Precursor 2i

Precursor 2i, 4-fluoro-7-bromo-6-azaindole, was prepared by the samemethod as Precursor 2e, using POBr₃ in the step B instead of POCl₃. MSm/z: (M+H)⁺ calcd for C₇H₅BrFN₂: 214.96. found 214.97. HPLC retentiontime: 1.28 minutes (column G).

Precursor 2j

To a mixture of 5-bromo-2-chloro-3-nitropyridine (10 g, 42 mmol) in1,4-dioxane (100 ml) was added pyrazole (5.8 g, 85 mmol). The resultingmixture was stirred at 120° C. for 26.5 h., and then evaporated aftercooling to r.t. The crude material was purified by flash chromatography(0 to 5% EtOAc/Hexanes) to give the desired product5-Bromo-3-nitro-2-pyrazol-1-yl-pyridine. ¹H NMR: (CD₃OD) δ 8.77 (s, 1H),8.56 (s, 1H), 8.45 (s, 1H), 7.73 (s, 1H), 6.57 (s, 1H); LC/MS: (ES+) m/z(M+H)⁺ =269, 271, HPLC R_(t)=1.223.

To a 250 mL round bottom flask was charged5-Bromo-3-nitro-2-pyrazol-1-yl-pyridine (1.02 g, 3.8 mmol) and THF (30ml). The mixture was then cooled to −78° C., and added a THF solution ofvinylmagnesium bromide (23 mL, 18.4 mmol, 0.8 114). After three minutes,the reaction mixture was warmed to −45° C. and remained stirring for 1h. The reaction was then quenched with ammonium chloride, and theresulting mixture extracted with EtOAc. The combined extracts wereevaporated in vacuo, and the residue purified by flash columnchromatography (5% EtOAc/Hexanes) to give compound 2 (which by HPLCcontained about 50% of a side product, presumably 3-vinylamino ofcompound 1); ¹H NMR: (CDCl₃) δ 10.75 (b s, 1H), 8.73 (s, 1H), 8.10 (s,1H), 7.82 (s, 1H), 7.52 (s, 1H), 6.67 (s, 1H), 6.53 (s, 1H); LC/MS:(ES+) m/z (M+H)=262, 264; HPLC R_(t)=1.670.

Precursor 2k

To a solution of 2-bromo-5-chloro-3-nitropyridine 5 (20 g, 84 mmol,prepared in 2 steps from 2-amino-5-chloropyridine as described inWO9622990) in THF (300 ml) at −78° C. was charged a THF solution ofvinylmagnesium bromide (280 ml, 252 mmol, 0.9 Ai). The resulting mixturewas stirred at −78° C. for one hour, followed by quenching with aqueousammonium chloride (500 ml, sat.) and extracted with EtOAc (5×500 ml).The combined organic extracts were washed with aqueous ammonium chloride(2×500 ml, sat.) and water (3×500 ml), dried (MgSO₄) and evaporated togive a brownish residue. The crude material was triturated with CH₂Cl₂,and the solid formed filtered to give compound 6 as a yellow solid (8.0g, 41%); ¹H NMR: (DMSO-d₆) 12.30 (b s, 1H), 7.99 (s, 1H), 7.80 (d,J=3.0, 1H), 6.71 (d, J=3.0, 1H); LC/MS: (ES+) m/z (M+H)⁺ =231, 233, 235;HPLC R_(t)=1.833.

Precursor 2m

4-Fluoro-7-Bromo-6-azaindole (500 mg, 1.74 mmol) was dissolved in THF (5ml) and cooled to −78° C. and n-BuLi (2.5 M, 2.1 ml) was added dropwise.The reaction mixture was stirred at −78° C. for 15 min, then stirred at0° C. for 30 min. The reaction was cooled to −78° C. again, and DMF (0.7ml, 8.7 mmol) was added. After stirring for 30 min, water was added toquench the reaction. The reaction mixture was extracted withethylacetate. The organic layer was dried over MgSO₄, filtered,concentrated and chromatographied to afford 208 mg of precursor 2m.LC/MS: (ES⁺) m/z (M+H)⁺ =164.98. Rt=0.44 min.

Precursor 2n

A mixture of precursor 2m (50 mg, 0.30 mmol), potassium carbonate (42mg, 0.30 mmol) and tosylmethyl isocyanide (60 mg, 0.30 mmol) in MeOH (3ml) was heated to reflux for about 2 hr. The solvent was removed invacuum and the residue was treated with ice water and extracted withether. The organic layer was washed with an aqueous solution of HCl(2%), water and dried over magnesium sulfate. After filtration andevaporation of the solvent, the residue was purified on silica to affordthe title compound (60 mg). LC/MS: (ES⁺) m/z (M+H)⁺ =204. Rt=0.77 min.

Precursor 2o

4-Fluoro-7-Bromo-6-azaindole (510 mg, 2.39 mmol) in anhydrous DMF (5 mL)was treated with copper cyanide (430 mg, 4.8 mmol) at 150° C. in a sealtube for 1 h. An aqueous solution of NH₄OH (10 mL) was added and thereaction was extracted with diethylether (2×50 mL) and ethylacetate(2×50 mL). The organic phases were combined and dried over sodiumsulfate, filtered, concentrated in vacuum and chromatographied on silicagel (gradient elution AcOEt/Hexanes 0-30%) to afford the title compoundas a brownish solid (255 mg, 66%) LC/MS: (ES⁺) m/z (M+H)⁺ =162.

Precursor 2p

Precursor 2o (82 mg, 0.51 mmol) was dissolved in absolute ethanol (200%proof, 5 mL) and treated with hydroxylamine hydrochloride (53 mg, 0.76mmol) and triethylamine (140 μL, 1.0 mmol) and the reaction mixture washeated up at 80° C. in a seal tube for 2 h. The solvent was removed invacuum and the pale yellow solid residue was washed with water to affordthe title compound. LC/MS: (ES⁺) m/z (M+H)⁺ =195. This compound wastaken to the next step without further purification.

Precursor 2q

Precursor 2p was dissolved in trimethylorthoformate (1 mL) and heated at85° C. in a seal tube for 1 h, then it was cooled to rt, the solvent wasremoved in vacuum and the residue was chromatographied on silica gel(AcOEt/Hexanes, gradient elution 10-60%) to afford the title compound(54 mg, LC/MS: (ES⁺) m/z (M+H)⁺ =205).

Precursor 2r

Precursor 2q (100 mg, 0.62 mmol, crude) in ethanol (5 mL) was treatedwith an aqueous solution of sodium hydroxide (50%, 2 mL) and thereaction mixture was heated at 110° C. overnight in a seal tube. The pHwas adjusted to 2 with HCl (6N) and a brown precipitate was filteredoff. The solution was concentrated to dryness to afford the titlecompound as a pale yellow solid LC/MS: (ES) m/z (M+H)⁺ =181. Thiscompound was used without further purification.

Precursor 2s

Precursor 2r (0.62 mmol) was dissolved in DMF (1 mL) and treated with3-aminopyridine (58.3 mg, 0.62 mmol), DEBT (185 mg, 0.62) and Hunig'sbase (216 μL, 1.26 mmol) and the reaction mixture was stirred at roomtemperature for 18 h. Water was added and the reaction was extractedwith AcOEt (2×25 mL) and CHCl₃ (2×25 mL), dried over sodium sulfate,concentrated and chromatographied on silica gel (AcOEt/Hexanes gradientelution 0-50%) to afford the title compound as a brownish solid LC/MS:(ES) m/z (M+H)⁺ =257.

Precursor 2s′

Precursor 2h, 4-methoxy-7-bromo-5-azaindole was prepared by the samemethod as Precursor 2a, starting from 2-methoxy-5-bromo-4-nitro-pyridine(precursor 1a). ¹H NMR (CDCl3) δ 8.52 (s, 1H), 7.84 (s, 1H), 7.12 (t,1H), 6.68 (d, 1H), 3.99 (s, 3H). LC MS showed desired M+H.

Precursor 2t

A mixture of aldehyde precursor 2m (150 mg, 0.91 mmol), sodium cyanide(44 mg, 0.091 mmol) and tosylmethyl isocyanide (177 mg, 0.91 mmol) inEtOH (3 ml) was stirred at room temperature for 30 min, then filteredand the crystals were washed with ether-hexane (1:1) and dried. Theobtained crystals, and a saturated solution of ammonia in dry methanol(8 ml) were heated between 100-110° C. for 16 hr. The mixture wasconcentrated and chromatographed to provide 20 mg of precursor 2. LC/MS:(ES) m/z (m+H)⁺ =203. Rt=0.64 min.

Precursor 3a

Typical Procedure for Acylation of Azaindole:

Preparation of Methyl (7-chloro-6-azaindol-3-yl)-oxoacetate, Precursor3a is an example of Step B of Scheme 1. 7-Chloro-6-azaindole, Precursor2a (0.5 g, 3.3 mmol) was added to a suspension of AlCl₃ (2.2 g, 16.3mmol) in CH₂Cl₂ (100 mL). Stirring was continued at rt for 10 minutesbefore methyl chlorooxoacetate (2.0 g, 16.3 mmol) was added dropwise.The reaction was stirred for 8 h. The reaction was quenched with icedaqueous NH₄OAc solution (10%, 200 mL). The aqueous phase was extractedwith CH₂Cl₂ (3×100 mL). The combined organic layer was dried over MgSO₄,filtered and the filtrate was concentrated in vacuo to give a residuewhich was carried to the next step without further purification.Precursor 2, Methyl (7-chloro-6-azaindol-3-yl)-oxoacetate: MS m/z:(M+H)⁺ calcd for C₁₀H₈ClN₂O₃: 239.02. found 238.97. HPLC retention time:1.07 minutes (column A).

Precursor 3b

Precursor 3b, Methyl (6-azaindol-3-yl)-oxoacetate, was prepared by thesame method as Precursor 3a, starting from 6-azaindole. MS m/z: (M+H)⁺calcd for C₁₀H₉N₂O₃: 205.06. found 205.14. HPLC retention time: 0.49minutes (column A).

Precursor 3c

Precursor 3c, Methyl (7-(4-methoxyphenyl)-4-azaindol-3-yl)-oxoacetate,was prepared by the same method as Precursor 3a, starting from7-(4-methoxyphenyl)-4-azaindole (Precursor 2b). MS m/z: (M+H)⁺ calcd forC₁₇H₁₅N₂O₄: 311.10. found 311.04. HPLC retention time: 1.15 minutes(column A).

Precursor 3d

Precursor 3d, methyl (7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetate wasprepared by the same method as Precursor 3a, starting from Precursor 2e,4-methoxy-7-chloro-6-azaindole. MS m/z: (M+H)⁺ calcd for C₁₂H₁₂ClN₂O₄:283.05. found 283.22. HPLC retention time: 1.37 minutes (column B).

Precursor 3e

Precursor 3e, Methyl (7-chloro-4-fluoro-6-azaindol-3-yl)-oxoacetate wasprepared by the same method as Precursor 3a starting from Precursor 2d,4-fluoro-7-chloro-6-azaindole. ¹H NMR (500 MHz, CD₃OD) δ 8.63 (s, 1H),8.00 (s, 1H), 3.95 (s, 3H). MS m/z: (M+H)⁺ calcd for C₁₀H₇ClFN₂O₃:257.01. found 257.00. HPLC retention time: 1.26 minutes (column A).

Precursor 3f

Precursor 3f, Methyl (7-chloro-4-azaindol-3-yl)-oxoacetate was preparedby the same method as Precursor 3a, starting from Precursor 2g,7-chloro-4-azaindole. MS m/z: (M+H)⁺ calcd for C₁₀H₈ClN₂O₃: 239.02.found 238.97. HPLC retention time: 0.60 minutes (column A).

Precursor 3g

Precursor 3g, Methyl (5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetate wasprepared by the same method as Precursor 3a, starting from Precursor 2h,5-chloro-7-methyl-4-azaindole. MS m/z: (M+H)⁺ calcd for C₁₁H₁₀ClN₂O₃:253.04. found 252.97. HPLC retention time: 1.48 minutes (column B).

Precursor 4a

Typical Procedure of Hydrolysis of Ester:

Preparation of Potassium (7-chloro-6-azaindol-3-yl)-oxoacetate,Precursor 4a, is an example of Step C of Scheme 1. Crude methyl(7-chloro-6-azaindol-3-yl)-oxoacetate, Precursor 3a, and an excess ofK₂CO₃ (2 g) were dissolved in MeOH (20 mL) and H₂O (20 mL). After 8 h,the solution was concentrated and the residue was purified by silica gelcolumn chromatography to provide 200 mg of Potassium(7-chloro-6-azaindol-3-yl)-oxoacetate. MS m/z: (M+H)⁺ of thecorresponding acid was observed. Calc'd for C₉H₆ClN₂O₃: 225.01. found225.05. HPLC retention time: 0.83 minutes (column A).

Precursor 4b

Potassium (6-azaindol-3-yl)oxoacetate, Precursor 4b, was prepared by thesame method as Precursor 4a, starting from Methyl(6-azaindol-3-yl)oxoacetate, Precursor 3b. MS m/z: (M+H)⁺ of thecorresponding acid was observed. Calc'd for C₉H₇N₂O₃: 191.05. Found190.99. HPLC retention time: 0.12 minutes (column A).

Precursor 4c

Precursor 4c, Potassium(7-(4-methoxyphenyl)-4-azaindol-3-yl)-oxoacetate, was prepared by thesame method as Precursor 4a, starting from Methyl(7-(4-methoxyphenyl)-4-azaindol-3-yl)-oxoacetate, Precursor 3c. MS m/z:(M-K+H)⁺ calcd for C₁₆H₁₃N₂O₄: 297.07. found 297.04. HPLC retentiontime: 1.00 minutes (column A).

Precursor 4d

Precursor 4d, Potassium (7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetatewas prepared by the same method as Precursor 4a starting from Methyl(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetate, Precursor 3d. MS m/z:(M+H)⁺ of the corresponding acid of compound 4d (M−K+H)⁺ calcd forC₁₀H₈ClN₂O₄: 255.02. found 255.07. HPLC retention time: 0.74 minutes(column A).

Precursor 4e

Precursor 4e, Potassium (7-chloro-4-azaindol-3-yl)-oxoacetate wasprepared by the same method as Precursor 4a, starting from Methyl(7-chloro-4-azaindol-3-yl)-oxoacetate, Precursor 3f. MS m/z: (M+H)⁺ ofthe corresponding acid of compound 4e (M−K+H)⁺ calcd for C₉H₆ClN₂O₃:225.01. found 225.27. HPLC retention time: 0.33 minutes (column A).

Precursor 4f

Precursor 4f, Potassium (5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetatewas prepared by the same method as Precursor 4a, starting from Methyl(5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetate, Precursor 3g. MS m/z:(M+H)⁺ of the corresponding acid of compound 4f (M−K+H)⁺ calcd forC₁₀H₈ClN₂O₃: 239.02. found 238.94. HPLC retention time: 1.24 minutes(column B).

Precursor 4g

Precursor 4g, Potassium (7-bromo-6-azaindol-3-yl)-oxoacetate wasprepared by the same method as Precursor 4a, starting from Methyl(7-bromo-6-azaindol-3-yl)-oxoacetate (prepared according to the methodof Precursor 3a from 7-Bromo-6-azaindole, Precursor 2f). ¹H NMR (500MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.16 (d, 1H, J=5.3 Hz), 8.08 (d, 1H,J=5.45 Hz); ¹³C NMR (125 MHz, DMSO-d₆) δ 180.5, 164.0, 141.6, 140.4,132.4, 125.3, 115.5, 113.0.

Precursor 4h

Precursor 4h, Potassium (7-bromo-4-fluoro-6-azaindol-3-yl)-oxoacetatewas prepared by the same method as Precursor 4a, starting from Methyl(7-bromo-4-fluoro-6-azaindol-3-yl)-oxoacetate (prepared according to themethod of Precursor 3a from 7-Bromo-4-fluoro-6-azaindole, Precursor 2i).MS m/z: (M+H)⁺ of the corresponding acid of compound 4 g (M−K+H)⁺ calcdfor C₉H₅BrFN₂O₃: 286.95. found 286.94. HPLC retention time: 0.94 minutes(column A).

Precursor 4i

1-ethyl-3-methylimidazolium chloride (0.172 g, 1.1 mmol) was added toaluminum chloride (0.560 g, 4.2 mmol), and the mixture vigorouslystirred. Upon formation of a liquid, precursor 2j was added, followed byethyl chlorooxoacetate (0.12 ml, 1.1 mmol). The mixture was allowed tostir at r.t. for 16 h, after which additional chlorooxoacetate was added(0.12 ml, 1.1 mmol). Following this addition, the reaction was allowedto stir at r.t. for another 24 h. The flask was cooled to 0° C. andwater added, upon which precipitates were formed. The solid material wasfiltered, washed with water and methanol, and dried under high vacuum togive compound 3; LC/MS: (ES+) m/z (M+H)=334, 336; HPLC R_(t)=1.390.

Precursor 4j

To 1-ethyl-3-methylimidazolium chloride (2.54 g, 17 3 mmol) was addedaluminum chloride (6.91 g, 51.8 mmol). The mixture was stirredvigorously at ambient temperature for ten minutes. To the resultingyellow liquid was added precursor 2k (2.0 g, 8.64 mmol) and ethylchlorooxoacetate (2.0 ml, 17 3 mmol), and was stirred at ambienttemperature for 16 h. The reaction mixture was then added ice/water (300ml) to give precipitates, which were filtered and washed with water togive the title compound as a yellow solid (1.98 g). The aqueous solutionwas extracted with EtOAc (3×300 ml), and the extracts evaporated invacuo to give a second batch of compound 8 as a yellow solid (439 mg,total yield 92%); ¹H NMR: (DMSO-d₆) 14.25 (b s, 1H), 13.37 (s, 1H), 8.56(s, 1H), 8.18 (s, 1H); LC/MS: (ES+) m/z (M+H)⁺ =303, 305, 307; HPLCR_(t)=1.360.

Precursor 4k

1-Ethyl-3-methylimidazolium chloride (82 mg, 0.56 mmol) was added to aflask which contained precursor 2n (56 mg, 0.28 mmol) and the mixturewas cooled to 0° C. Aluminum chloride (336 mg, 2.52 mmol) was added inone portion followed by ClCOCOOEt (58 μL, 0.56 mmol) and the reactionmixture was stirred at room temperature for 2 days. Ice water was addedto quench the reaction. The reaction mixture was filtered. The solid waswashed with water and diethylether and dried in air to afford the titlecompound (58 mg). LC/MS: (ES) m/z (M+H)⁺ =276. Rt=0.85 min.

Precursor 4m

1-Ethyl-3-methylimidazolium chloride (73 mg, 0.52 mmol) and aluminumchloride (198 mg, 1.56 mmol) were stirred together under nitrogen for 1h. To this solution was added intermediate 2q (54 mg, 0.26 mmol) andethyloxalylchloride (58 μL, 0.52 mmol) and the reaction mixture wasstirred at rt for 18 h. The reaction was quenched with water and themixture was stirred for 15 min. The solid was collected by filtrationand washed with water and diethylether. LC/MS (ES⁺) m/z (M+H)⁺ =276.This compound was used without further purification.

Precursor 4n

1-Ethyl-3-methylimidazolium chloride (26 mg, 0.18 mmol) was added to aflask which contained precursor 2t (18 mg, 0.09 mmol) and the mixturewas cooled to 0° C. Aluminum chloride (92 mg, 0.54 mmol) was added inone portion followed by ClCOCOOEt (20 μL, 0.18 mmol) and the reactionmixture was stirred at room temperature for 2 days. Ice water was addedto quench the reaction. The reaction mixture was filtered. The solid waswashed with water and diethylether and dried in air to afford compound D(18 mg). LC/MS: (ES⁺) m/z (m+H)⁺ =275. Rt=0.49 min.

Precursor 5a

Typical Procedure for Coupling Piperazine Derivative and Azaindole Acid:

Preparation of1-benzoyl-3-(R)-methyl-4-[(7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine,Precursor 5, is an example of Step D of Scheme 1. Potassium7-chloro-6-azaindole 3-glyoxylate, Precursor 4a, (100 mg, 0.44 mmol),3-(R)-methyl-1-benzoylpiperazine (107 mg, 0.44 mol),3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) (101 mg,0.44 mol) and Hunig's Base (diisopropylethylamine, 0.5 mL) were combinedin 5 mL of DMF. The mixture was stirred at rt for 8 h. DMF was removedvia evaporation at reduced pressure and the residue was purified using aShimadzu automated preparative HPLC System to give1-(benzoyl)-3-(R)-methyl-4-[(7-chloro-6-azaindol-3-yl)-oxoacetyl]-piperazine(70 mg, 39%). MS m/z: (M+H)⁺ Calc'd for C₂₁H₂₀ClN₄O₃: 411.12. Found411.06. HPLC retention time: 1.32 minutes (column A).

Precursor 5b

Precursor 5b,1-benzoyl-4-[(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetyl]piperazinewas prepared by the same method as Precursor 5a starting from Potassium(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetate, Precursor 4d, and1-benzoylpiperazine. MS m/z: (M+H)⁺ calcd for C₂₁H₂₀ClN₄O₄: 427.12.found 427.12. HPLC retention time: 1.28 minutes (column A).

Precursor 5c

Precursor 5c,1-benzoyl-3-(R)-methyl-4-[(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetyl]piperazinewas prepared by the same method as Precursor 5a starting from Potassium(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetate, Precursor 4d, and1-benzoylpiperazine. ¹H NMR (500 MHz, CDCl₃) δ 8.10 (s, 1H), 7.72 (s,1H), 7.40 (s, 5H), 3.89 (s, 3H), 3.71-3.40 (m, 8H). MS m/z: (M+H)⁺ calcdfor C₂₂H₂₂ClN₄O₄: 441.13. found 441.17. HPLC retention time: 1.33minutes (column A).

Precursor 5d

Precursor 5d,1-benzoyl-3-(R)-methyl-4-[(7-chloro-4-azaindol-3-yl)-oxoacetyl]piperazinewas prepared by the same method as Precursor 5a, starting from Potassium(7-chloro-4-azaindol-3-yl)-oxoacetate, Precursor 4e, and1-benzoyl-3-(R)-methyl piperazine. MS m/z: (M+H)⁺ calcd for C₂₁H₂₀ClN₄O₃411.12. found 411.04. HPLC retention time: 1.10 minutes (column A).

Precursor 5e

Precursor 5e,1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetyl]piperazinewas prepared by the same method as Precursor 5a, starting from Potassium(5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetate, Precursor 4f, and1-benzoyl-3-(R)-methyl piperazine. MS m/z: (M+H)⁺ calcd for C₂₂H₂₂ClN₄O₃425.24. found 425.04. HPLC retention time: 1.72 minutes (column B).

Precursor 5f

Precursor 5f,1-benzoyl-3-(R)-methyl-4-[(7-bromo-6-azaindol-3-yl)-oxoacetyl]piperazinewas prepared by the same method as Precursor 5a, starting from(7-bromo-6-azaindol-3-yl)-oxoacetic acid potassium salt, Precursor 4g,and 1-benzoyl-3-(R)-methylpiperazine. MS m/z: (M+H)⁺ calcd forC₂₁H₂₀BrN₄O₃: 455.07. found 455.14. HPLC retention time: 1.45 minutes(column B).

Precursor 5g

Precursor 5g,1-benzoyl-4-[(7-bromo-6-azaindol-3-yl)-oxoacetyl]piperazine was preparedby the same method as Precursor 5a, starting from(7-bromo-6-azaindol-3-yl)-oxoacetic acid potassium salt, Precursor 4g,and 1-benzoylpiperazine. MS m/z: (M+H)⁺ calcd for C₂₀H₁₈BrN₄O₃: 441.06.found 441.07. HPLC retention time: 1.43 minutes (column B).

Precursor 5h

Precursor 5h,1-benzoyl-3-(R)-methyl-4-[(6-azaindol-3-yl)-oxoacetyl]piperazine wasprepared by the same method as Precursor 5a starting from Potassium(6-azaindol-3-yl)oxoacetate, Precursor 4b, and1-benzoyl-3-(R)-methylpiperazine. MS m/z: (M+H)⁺ Calc'd for C₂₁H₂₁N₄O₃:377.16. Found 377.10. HPLC retention time: 0.88 minutes (column A).

Precursor 5i

Addition of precursor 2d to a solution of aluminum trichloride indichloromethane stirring at ambient temperature followed 30 minuteslater with chloromethyl or chloroethyl oxalate (according to the methoddescribed for precursor 3a) provides either the methyl or ethyl ester,respectively. Hydrolysis with KOH (as in the standard hydrolysisprocedure described for precursor 4a) provided potassium(7-chloro-4-fluoro-6-azaindol-3-yl)oxoacetate. Potassium(7-chloro-4-fluoro-6-azaindol-3-yl)oxoacetate was then reacted with1-benzoyl piperazine in the presence of DEPBT under the standardconditions (as described for precursor 5a) to provide1-benzoyl-4-[(4-fluoro-7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine,precursor 5i. ¹H NMR (500 MHz, CD₃OD) δ 8.40 (s, 1H), 8.04 (s, 1H), 7.46(bs, 5H), 3.80-3.50 (m, 8H); LC/MS (ES) m/z (M+H)⁺ 415 observed;retention time 1.247 minutes; LC/MS method: YMC ODS-A C18 S7 3.0×50 mmcolumn; Start % B=0, Final % B=100, Gradient time=2 minutes; Flow rate=5mL/min; detector wavelength=220 nm.

Precursor 5j

1-benzoyl-3-(R)-methyl-4-[(4-fluoro-7-chloro-6-azaindol-3-yl)-oxoacetyl]-piperazinewas prepared by coupling potassium(7-chloro-4-fluoro-6-azaindol-3-yl)oxoacetate, prepared as describedabove for precursor 5i, with 1-benzoyl-3-(R)-methylpiperazine in thepresence of DEPBT under the standard conditions (as described forprecursor 5a) to provide1-benzoyl-3-(R)-methyl-4-[(4-fluoro-7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine,precursor 5j. ¹H NMR (500 MHz, CD₃OD) δ 8.42, 8.37 (s, s, 1H), 8.03 (s,1H), 7.71-7.45 (m, 5H), 4.72-3.05 (m, 7H), 1.45-1.28 (m, 3H); LC/MS(ES⁺) m/z (M+H)⁺ 429 observed; retention time 1.297 minutes; LC/MSmethod: YMC ODS-A C18 S7 3.0×50 mm column; Start % B=0, Final % B=100,Gradient time=2 minutes; Flow rate=5 mL/min; detector wavelength=220 nm.

Precursor 5k

Precursor 5k,1-benzoyl-4-[(7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine wasprepared by the same method as Precursor 5a, starting from(7-chloro-6-azaindol-3-yl)-oxoacetic acid potassium salt, Precursor 4a,and 1-benzoylpiperazine. MS m/z: (M+H)⁺ calcd for C₂₀H₁₈ClN₄O₃: 397.11.found 396.97. HPLC retention time: 2.37 minutes (column F, gradienttime=3 min, flow rate=4 ml/min).

Precursor 5l

Precursor 5l,1-picolinoyl-4-[(4-methoxy-7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazinewas prepared by the same method as Precursor 5a starting from Potassium(4-methoxy-7-chloro-6-azaindol-3-yl)oxoacetate, Precursor 4d, andpicolinoyl-piperazine. ¹H NMR (500 MHz, DMSO-d₆) 68.63-7.45 (m, 7H),3.94 (s, 3H), 3.82-2.50 (m, 8H). MS m/z: (M+H)⁺ Calc'd for C₂₀H₁₉ClN₅O₄:428.11. Found 428.11. HPLC retention time: 1.09 minutes (column A).

Precursor 5m

Precursor 5m,(R)-1-picolinoyl-3-methyl-4-[(7-bromo-6-azaindol-3-yl)-oxoacetyl]piperazinewas prepared by the same method as Precursor 5a starting from Potassium(7-bromo-6-azaindol-3-yl)oxoacetate, Precursor 4g, and(R)-3-methyl-1-picolinoyl-piperazine. MS m/z: (M+H)⁺ Calc'd forC₂₀H₁₉BrN₅O₃: 456.07. Found 456.11. HPLC retention time: 1.12 minutes(column A).

Precursor 5n

Precursor 5n,(S)-1-picolinoyl-3-methyl-4-[(7-bromo-6-azaindol-3-yl)-oxoacetyl]piperazinewas prepared by the same method as Precursor 5a starting from Potassium(7-bromo-6-azaindol-3-yl)oxoacetate, Precursor 4g, and(S)-3-methyl-1-picolinoyl-piperazine. ¹H NMR (500 MHz, CDCl₃) 68.63-7.36(m, 7H), 5.02-3.06 (m, 7H), 1.42-1.26 (m, 3H).

Precursor 5o

Precursor 5o,(R)-1-picolinoyl-3-methyl-4-[(7-bromo-4-fluoro-6-azaindol-3-yl)-oxoacetyl]piperazinewas prepared by the same method as Precursor 5a starting from Potassium(7-bromo-4-fluoro-6-azaindol-3-yl)oxoacetate, Precursor 4h, and(R)-3-methyl-1-picolinoyl-piperazine. ¹H NMR (500 MHz, CD₃OD) δ8.68-7.52(m, 6H), 4.94-2.69 (m, 7H), 1.48-1.24 (m, 3H). MS m/z: (M+H)⁺ Calc'd forC₂₀H₁₈BrFN₅O₃: 474.06. Found 474.23. HPLC retention time: 1.20 minutes(column A).

Precursor 5p

Precursor 5p,1-benzoyl-4-[(7-chloro-4-azaindol-3-yl)-oxoacetyl]piperazine wasprepared by the same method as Precursor 5a starting from Potassium(7-chloro-4-fluoro-4-azaindol-3-yl)oxoacetate, Precursor 4e, and1-benzoyl-piperazine. ¹H NMR (500 MHz, CD₃OD) δ8.83 (s, 1H), 8.63 (d,1H, J=5.35 Hz), 7.91 (d, 1H, J=5.75 Hz), 7.47 (m, 5H), 3.80-3.30 (m,3H). MS m/z: (M+H)⁺ Calc'd for C₂₀H₁₈ClN₄O₃: 397.11. Found 397.02. HPLCretention time: 1.20 minutes (column A).

Precursor 5q

Precursor 5q,1-(4-Benzoyl-piperazin-1-yl)-2-(7-bromo-1H-pyrrolo[2,3-c]pyridin-3-yl)-ethane-1,2-dione

To a solution of acid precursor 4j (2.4 g, 7 9 mmol) in DMF (40 ml) wasadded 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT,5.96 g, 19 9 mmol), benzoylpiperazine hydrochloride (2.71 g, 11 9 mmol),and N,N-diisopropylethylamine (14 ml, 80.4 mmol). The mixture wasstirred at ambient temperature for 16 h. The reaction mixture was thenadded water (400 ml) and extracted with EtOAc (4×300 ml). The combinedextracts were evaporated in vacuo to give a brownish residue, which wastriturated with MeOH to provide the title compound as a white solid (2.8g, 74%); ¹H NMR: (DMSO-d₆) 13.41 (s, 1H), 8.48 (s, 1H), 8.19 (s, 1H),7.45 (b s, 5H), 3.80-3.35 (b m, 8H); LC/MS: (ES+) m/z (M+H)⁺ =475, 477,479; HPLC (alternate conditions B, column G) R_(t)=1.953.

Precursor 5r

Precursor 5r was prepared by procedure used for 5q using mono N-Bocpiperazine. ¹H NMR: (CDCl₃) δ 8.26 (s, 1H), 8.19 (s, 1H), 3.71 (b s,2H), 3.53 (b m, 6H), 1.48 (s, 9H); LC/MS: (ES+) m/z (M+H)⁺ =471, 473,475; HPLC (alternate conditions B, column G) R_(t)=1.543.

Precursor 5s

Precursor 5s was prepared by procedure used for 5b using mono N-Bocpiperazine. MS m/z: (M+H)⁺ Calc'd for C₁₉H₂₄ClN₄O₅: 423.14. Found 423.07HPLC retention time: 1.44 minutes (column L).

Precursor 5t

Precursor 5t, was prepared from Precursor 5s and the pyrazin-2-ylstannane, via the procedure described in the later section Preparationof Compounds of Formula I. MS m/z: (M+H)⁺ Calc'd for C₂₃H₂₇N₆O₅: 467.20.found 467.47. HPLC retention time: 1.57 minutes (column C).

Precursor 5u

Preparation of precursor 5u: Precursor 5t (30 mg) was dissolved in TFA(0.5 g). After the reaction was stirred for 30 minutes, the mixture wasconcentrated in vacuo to give the desired intermediate 5u which was usedin further reactions without any purification. MS m/z: (M+H)⁺ Calc'd forC₁₈H₁₉N₆O₅: 367.15. found 367.06. HPLC retention time: 0.91 minutes(column M).

Precursor 5v

Precursor 5v was prepared by procedure used for 5b using2-methyl-1-picolinoylpiperazine. MS m/z: (M+H)⁺ Calc'd for C₂₁H₂₁ClN₅O₄:442.13. Found 442.11. HPLC retention time: 1.01 minutes (column G).

Precursor 5xa

Precursor 5xa was prepared by procedure used for 5b using(R)-2-methyl-1-picolinoylpiperazine. MS m/z: (M+H)⁺ Calc'd forC₂₁H₂₁ClN₅O₄: 442.13. Found 442.23. HPLC retention time: 1.12 minutes(column L).

Precursor 5y

Precursor 5y was prepared by procedure used for 5b using(R)-2-methyl-1-nicotinoylpiperazine. MS m/z: (M+H)⁺ Calc'd forC₂₁H₂₁ClN₅O₄: 442.13. Found 442.15. HPLC retention time: 0.87 minutes(column C).

Precursor 5z

Precursor 5z was prepared by procedure used for 5b using(R)-2-methyl-1-benzoylpiperazine. MS m/z: (M+H)⁺ Calc'd forC₂₂H₂₂ClN₄O₄: 441.13. Found 441.46. HPLC retention time: 1.27 minutes(column C).

Precursor 6

Typical Procedure for N-Oxide Formation:

Preparation of1-benzoyl-3-(R)-methyl-4-[(6-oxide-6-azaindol-3-yl)-oxoacetyl]piperazine,Precursor 6. 20 mg of1-benzoyl-3-(R)-methyl-4-[(6-azaindol-3-yl)-oxoacetyl]piperazine,Precursor 5h, (0.053 mmol) was dissolved in CH₂Cl₂ (2 mL). 18 mg ofmCPBA (0.11 mmol) was then added into the solution and the reaction wasstirred for 12 h at rt. CH₂Cl₂ was removed via evaporation at reducedpressure and the residue was purified using a Shimadzu automatedpreparative HPLC System to give the compound shown above (5.4 mg, 26%).MS m/z: (M+H)⁺ Calc'd for C₂₁H₂₁N₄O₄: 393.16. Found 393.11. HPLCretention time: 0.90 minutes (column A).

Precursor 7

Preparation of1-benzoyl-3-(R)-methyl-4-[(6-methyl-7-azaindol-3-yl)-oxoacetyl]-piperazineor1-benzoyl-3-(R)-methyl-4-[(4-methyl-7-azaindol-3-yl)-oxoacetyl]-piperazine.An excess of MeMgI (3M in THF, 0.21 ml, 0.63 mmol) was added into asolution of1-benzoyl-3-(R)-methyl-4-[(6-oxide-6-azaindol-3-yl)-oxoacetyl]piperazine,Precursor 6, (25 mg, 0.064 mmol). The reaction mixture was stirred at rtand then quenched with MeOH. The solvents were removed under vacuum, theresidue was diluted with MeOH and purified using a Shimadzu automatedpreparative HPLC System to give a compound shown above which was asingle isomer but regiochemistry was not definitively assigned. (6.7 mg,27%). MS m/z: (M+H)⁺ Calc'd for C₂₂H₂₃N₄O₃: 391.18. Found 391.17. HPLCretention time: 1.35 minutes (column B).

Precursor 8

1-benzoyl-3-(R)-methyl-4-[(6-phenyl-7-azaindol-3-yl)-oxoacetyl]piperazineor1-benzoyl-3-(R)-methyl-4-[(4-phenyl-7-azaindol-3-yl)-oxoacetyl]piperazine(regiochemistry was not definitively assigned) were prepared by themethod described for Example 7 starting with1-benzoyl-3-(R)-methyl-4-[(6-oxide-6-azaindol-3-yl)-oxoacetyl]piperazine,Precursor 6, and phenyl magnesium bromide (phenyl Grignard reagent). MSm/z: (M+H)⁺ Calc'd for C₂₇H₂₅N₄O₃: 453.19. Found 454.20. HPLC retentiontime: 1.46 minutes (column B).

Precursor 9

A mixture of Pd (10% on carbon, 100 mg), trifluoroacetic acid (1 mL) and1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetyl]piperazine,Precursor 5e (1.5 g) in MeOH (50 mL) and EtOAc (50 mL) was shaken in aParr reactor under a hydrogen atmosphere (45 psi) for 48 hours. Aftersolids were removed via filtration, the filtrate was concentrated invacuo to afford precursor 9 (1 g) which was used without furtherpurification. MS m/z: (M+H)⁺ calcd for C₂₁H₂₁N₄O₃ 391.18. found 391.15.HPLC retention time: 1.15 minutes (column A).

Precursors 10 and 11

Preparation of Precursor 10,1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-carbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazineand Precursor 11,1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-hydroxycarbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazine:A mixture of1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetyl]piperazine(1.78 g) and SeO₂ (4.7 g) in dioxane/water (100:1) was refluxed for 10hours. After cooling to room temperature, the mixture was concentratedin vacuo to provide a residue. The residue was purified by using silicagel chromatography with EtOAc and MeOH as eluting solvents to affordprecursor 10 (350 mg) and precursor 11 (410 mg). Precursor 10,1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-carbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₂H₂₀ClN₄O₄: 439.12. found 439.01. HPLCretention time: 1.37 minutes (column A); Precursor 11,1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-hydroxycarbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₂H₂₀ClN₄O₅: 455.11. found 455.10. HPLCretention time: 1.44 minutes (column A).

Precursors 12 and 13

Precursor 12,1-benzoyl-3-(R)-methyl-4-[(7-carbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazineand Precursor 13,1-benzoyl-3-(R)-methyl-4-[(7-hydroxycarbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazinewere made according to the same procedure of preparing Precursors 10 and11, by using Precursor 9 as a starting material. Precursor 12,1-benzoyl-3-(R)-methyl-4-[(7-carbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₂H₂₁N₄O₄: 405.16. found 405.14. HPLCretention time: 0.91 minutes (column A); Precursor 13,1-benzoyl-3-(R)-methyl-4-[(7-hydroxycarbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₂H₂₁N₄O₅: 421.15. found 421.09. HPLCretention time: 1.02 minutes (column A).

Precursors 14a-1-14a-21

The following tin agents and boron agents can be purchased fromcommercial resources and used without any further treatment (Table I-1).

TABLE I-1 Precursor Number Structure Company 14a-1 

Frontier Scientific, Inc. 14a-2 

Maybridge Chem. Co. 14a-3 

Frontier Scientific, Inc. 14a-4 

Matrix Scientific 14a-5 

Matrix Scientific 14a-6 

Aldrich, Co. 14a-7 

Aldrich, Co. 14a-8 

Aldrich, Co. 14a-9 

Aldrich, Co. 14a-10

Aldrich, Co. 14a-11

Lancaster 14a-12

Aldrich, Co. 14a-13

Aldrich, Co. 14a-14

Frontier Scientific, Inc. 14a-15

Matrix Scientific 14a-16

Frontier Scientific, Inc. 14a-17

Riedel-de Haen AG 14a-18

Lancaster 14a-19

Lancaster 14a-20

Aldrich, Co. 14a-21

Frontier Scientific, Inc.

Preparation of Tin Agents: Precursors 14-1-14-65

The following known tin agents and boron agents could be preparedaccording to the documented procedures indicated without anymodification (Table I-2):

TABLE I-2 Precursor Number Structure Reference 14-1 

Dondoni, A., et al Synthesis, 1987, 693 14-2 

Aldous, D. J., et al U.S. Pat. No. 5,453,433 14-3 

Sandosham, J., et al Tetrahedron 1994, 50, 275. 14-4 

Lehn, L. M., et al. Chem. Eur. J. 2000, 6, 4133. 14-5 

Jutzi, P., et al J. Organometallic Chem. 1983, 246, 163. 14-6 

Jutzi, P., et al J. Organometallic Chem. 1983, 246, 163. 14-7 

Graybill, T. L., et al Bioorg. Med. Chem. Lett. 1995, 5 (4), 387. 14-8 

Heldmann, D. K., et al Tetrahedron Lett. 1997, 38, 5791. 14-9 

Kennedy, G., et al Tetrahedron Lett. 1996, 37, 7611. 14-10

Kondo, Y., et al Tetrahedron Lett. 1989, 30, 4249 14-11

Kondo, Y., et al Tetrahedron Lett. 1989, 30, 4249 14-12

Or, Y. S., et al U.S. Pat. No. 6,054,435 14-13

Or, Y. S., et al U.S. Pat. No. 6,054,435 14-14

Okada, T., et al WO-0123383 14-15

Okada, T., et al WO-0123383 14-16

Sandosham, J., et al Tetrahedron 1994, 50, 275 14-17

Sandosham, J., et al Acta Chem. Scand. 1989, 43, 684. 14-18

Nicolaou, K. C., et al WO-9967252 14-19

Nicolaou, K. C., et al WO-9967252 14-20

Nicolaou, K. C., et al WO-9967252 14-21

Benheda, R., et al Tetrahedron Lett. 1999, 40, 5701. 14-22

Collins, I., et al Tetrahedron Lett. 1999, 40, 4069. 14-23

Fuss, R. W., et al DE-19502178 14-24

Bunnage, M. E. et. al PCT Int. Appl. WO 0024745 A1 (2000); andSandosham, J. et. Al Tetrahedron (1994), 50(1), 275-84. 14-25

From 5-iodo2-chloro-1,3 pyrimidine. Fluoropyrimidines are obtained byfluorination of chloropyrimidines with CsF in N-methyl-2- pyrrolidinoneor DMF 2.5-63 h at 80-150° C. The iodo is then converted to the lithiumreagent with tBuLi and trapped with Bu₃SnCl. See Sandosham above. 14-26

Arukwe, J.; Benneche, T.; Undheim, K. J. Chem. Soc., Perkin Trans. 1(1989), (2), 255-9. 14-27

Fruit, C.; et. al. Heterocycles (1999), 51(10), 2349-2365. 14-28

Ziener, U.; et. al. Chem.- Eur. J. (2000), 6(22), 4132-4139. 14-29

Turck, A.; et. al Lab.. J. Organomet. Chem. (1991), 412(3), 301-10.Metallation of 2,6- dicloropyrazine and quench with Bu₃SnCl. 14-30

Ueno, K.; Sasaki, A.; Kawano, K.; Okabe, T.; Kitazawa, N.; Takahashi,K.; Yamamoto, N.; Suzuki, Y.; Matsunaga, M.; Kubota, A. PCT Int. Appl.WO 9918077 A1 (1999). 14-31

Fensome, A.; Miller, L. L.; Ullrich, J. W.; Bender, R. H. W.; Zhang, P.;Wrobel, J. E.; Zhi, L.; Jones, T. K.; Marschke, K. B.; Tegley, C. M. PCTInt. Appl. WO 0066556 A1 (2000). 14-32

Maw, G. N.; Middleton, D. S. Jpn. Kokai Tokkyo Koho JP 2000016984 A2(2000). 14-33

Chem. Pharm. Bull. (1998), 46(3), 400-412. 14-34

Hayashi, K.; Kito, T.; Mitsuyama, J.; Yamakawa, T.; Kuroda, H.;Kawafuchi, H. PCT Int. Appl. WO 9951588 A1 (1999). 14-35

Brown, A. D.; Dickinson, R. P.; Wythes, M. J. PCT Int. Appl. WO 9321178A1 (1993). 14-36

Brown, A. D.; Dickinson, R. P.; Wythes, M. J. PCT Int. Appl. WO 9321178A1 (1993). 14-37

Zalutsky, M. R. PCT Int. Appl. WO 0032240 A2 (2000). 14-38

Brown, A. D.; Dickinson, R. P.; Wythes, M. J. PCT Int. Appl. WO 9321178A1 (1993). 14-39

North, P. C.; Wadman, S. N. PCT Int. Appl. WO 9408993 A1 (1994). 14-40

North, P. C.; Wadman, S. N. PCT Int. Appl. WO 9408993 A1 (1994.) 14-41

Achab, S.; Guyot, M.; Potier, P. Tetrahedron Lett. (1993), 34(13),2127-30. 14-42

Muratake, H.; Tonegawa, M.; Natsume, M... Chem. Pharm. Bull. (1998),46(3), 400-412. Dehmlow, E. V.; Sleegers, A. Liebigs Ann. Chem. (1992),(9), 953-9. 14-43

Proudfoot, J. R.; Hargrave, K.; Kapadia, S. PCT Int. Appl. WO 9907379 A1(1999); and Chem. Pharm. Bull. (1998), 46(3), 400- 412. 14-44

Cruskie, M. P. Jr.; Zoltewicz, J. A.; Abboud, K. A. J. Org. Chem.(1995), 60(23), 7491-5. 14-45

Muratake, H.; et. al Chem. Pharm. Bull. (1998), 46(3), 400-412. 14-46

Muratake, H.; Tonegawa, M.; Natsume, M. Chem. Pharm. Bull. (1998),46(3), 400-412. Dolle, R. E.; Graybill, T. L.; Osifo, I. K.; Harris, A.L.; Miller, M. S.; Gregory, J. S. U. S. U. S. Pat. No. 5622967 (1997).14-47

Henze, O.; Lehmann, U.; Schlueter, A. D. Synthesis (1999), (4), 683-687.14-48

Hayashi, K.; Kito, T.; Mitsuyama, J.; Yamakawa, T.; Kuroda, H.;Kawafuchi, H. PCT Int. Appl. WO 9951588 A1 (1999); Reuman, M.; Daum, S.J.; Singh, B.; Wentland, M. P.; Perni, R. B.; Pennock, P.; Carabateas,P. M.; Gruett, M. D.; Saindane, M. T.; et al. J. Med. Chem. (1995),38(14), 2531-40. 14-49

Barros, M. T.; Maycock, C. D.; Ventura, M. R. Tetrahedron Lett. (1999),40(3), 557-560. Sirisoma, N. S.; Johnson, C. R. Tetrahedron Lett.(1998), 39(15), 2059- 2062. Trost, B. M.; Cook, G. R Tetrahedron Lett.(1996), 37(42), 7485- 7488. 14-50

Bunnage, M. E.; Maw, G. N.; Rawson, D. J.; Wood, A.; Mathias, J. P.;Street, S. D. A. PCT Int. Appl. WO 0024745 A1 (2000). 14-51

Bunnage, M. E.; Maw, G. N.; Rawson, D. J.; Wood, A.; Mathias, J. P.;Street, S. D. A. PCT Int. Appl. WO 0024745 A1 (2000). 14-52

Hayashi, K.; Kito, T.; Mitsuyama, J.; Yamakawa, T.; Kuroda, H.;Kawafuchi, H. PCT Int. Appl. WO 9951588 A1 (1999); and Sirisoma, N. S.;Johnson, C. R. Tetrahedron Lett. (1998), 39(15), 2059- 2062. 14-53

Schnatterer, S.; Kern, M.; Sanft, U. PCT Int. Appl. WO 9965901 A1(1999). 14-54

Hayashi, K.; Kito, T.; Mitsuyama, J.; Yamakawa, T.; Kuroda, H.;Kawafuchi, H. PCT Int. Appl. WO 9951588 A1 (1999). 14-55

Betageri, R.; Breitfelder, S.; Cirillo, P. F.; Gilmore, T. A.; Hickey,E. R.; Kirrane, T. M.; Moriak, M. H.; Moss, N.; Patel, U. R.; Proudfoot,J. R.; Regan, J. R.; Sharma, R.; Sun, S.; Swinamer, A. D.; Takahashi, H.PCT Int. Appl. WO 0055139 A2 (2000). 14-56

Ueno, K.; Sasaki, A.; Kawano, K.; Okabe, T.; Kitazawa, N.; Takahashi,K.; Yamamoto, N.; Suzuki, Y.; Matsunaga, M.; Kubota, A. PCT Int. Appl.WO 9918077 A1 (1999). 14-57

Calderwood, D.; Arnold, L. D.; Mazdiyasni, H.; Hirst, G.; Deng, B. B.PCT Int. Appl. WO 0017202 A1 (2000). 14-58

Hayashi, K.; Kito, T.; Mitsuyama, J.; Yamakawa, T.; Kuroda, H.;Kawafuchi, H. PCT Int. Appl. WO 9951588 A1 (1999). 14-59

Saji, H.; Watanabe, A.; Magata, Y.; Ohmono, Y.; Kiyono, Y.; Yamada, Y.;Iida, Y.; Yonekura, H.; Konishi, J.; Yokoyama, A. Chem. Pharm. Bull.(1997), 45(2), 284-290. 14-60

Hayashi, K.; Kito, T.; Mitsuyama, J.; Yamakawa, T.; Kuroda, H.;Kawafuchi, H. PCT Int. Appl. WO 9951588 A1 (1999); Reuman, M.; Daum, S.J.; Singh, B.; Wentland, M. P.; Perni, R. B.; Pennock, P.; Carabateas,P. M.; Gruett, M. D.; Saindane, M. T.; et al. J. Med. Chem. (1995),38(14), 2531-40. 14-61

Iino, Y.; Fujita, K.; Kodaira, A.; Hatanaka, T.; Takehana, K.;Kobayashi, T.; Konishi, A.; Yamamoto, T. PCT Int. Appl. WO 0102359 A1(2001). 14-62

Iino, Y.; Fujita, K.; Kodaira, A.; Hatanaka, T.; Takehana, K.;Kobayashi, T.; Konishi, A.; Yamamoto, T. PCT Int. Appl. WO 0102359 A1(2001). 14-63

Torrado, A.; Imperiali, B. J. Org. Chem. (1996), 61(25), 8940-8948.14-64

Iino, Y.; Fujita, K.; Kodaira, A.; Hatanaka, T.; Takehana, K.;Kobayashi, T.; Konishi, A.; Yamamoto, T. PCT Int. Appl. WO 0102359 A1(2001). 14-65

Gros, P.; Fort, Y. Synthesis (1999), (5), 754-756 and Gros, P.; Fort,Y.; Caubere, P. J. Chem. Soc., Perkin Trans. 1 (1997), (20), 3071- 3080.

Precursor 14-66

Preparation of 2,3-dicloro-5-(tri-n-butylstannyl)pyrazine (An example ofgeneral procedure Tin-01, below): TMP-Li (2,2,6,6-tetramethylpiperidinyllithium) was prepared by addition of n-butyl lithium (1.6 M, 6.25 mL) toa solution of 2,2,4,4-tetramethylpiperidine (1.4 g) in dry THF (180 mL)at −78° C. The solution was then allowed to warm to 0° C., was stirredat 0° C. for 15 minutes, then was cooled to −78° C. To the solution wasadded 2,3-dichloropyrazine (1.35 g), and followed by an addition oftri-n-butyltin chloride (3.25 g) in another 2 hours. The reaction wasquenched with aqueous ammonium chloride solution. The organic layer wasseparated, and aqueous layer was extracted with ethyl acetate (3×100mL). The combined organic extract was dried over magnesium sulfate,filtered and the filtrate concentrated in vacuo. The residue waspurified by silica gel chromatography to afford2,3-dicloro-5-(tri-n-butylstannyl)pyrazine (1 g).

Precursor 14-67

Preparation of 2-(tri-n-butylstannyl)-pyrimidine: (Example of thegeneral procedure Tin-03, below) Tri-n-butylstannyl lithium was preparedat 0° C. in dry THF (20 mL) from tri-butyltin hydride (2.2 mL) and LDA(lithium diisopropylamide, 2M, 4.09 mL). The tri-n-butylstannyl lithiumsolution was then cooled to −78° C. and to it was added2-bromopyrimidine (1 g). The reaction mixture was then allowed to warmup to room temperature over 8 hours. The reaction was then quenched withaqueous ammonium chloride solution. The organic layer was separated, andaqueous layer was extracted with ethyl acetate (3×20 mL). The combinedorganic layer was dried over magnesium sulfate, filtered and thefiltrate concentrated in vacuo. The residue was purified by silica gelchromatography to afford 2-(tri-n-butylstannyl)-pyrimidine (190 mg).

Precursor 14-68

Preparation of 2-amino-6-(tri-n-butylstannyl)pyrazine (Example of thegeneral procedure Tin-04, below): To a sealed tube,2-amino-6-chloro-pyrazine (1 g), bis(tri-butyltin) (3.92 mL) andtetrakis-triphenylphosphine palladium, Pd(Ph₃P)₄ (100 mg) were combinedin dioxane (10 mL). The reaction was heated at 110-120° C. for 10 h.After the mixture cooled down to room temperature, it was poured into 20mL of water. The solution was extracted with EtOAc (4×20 mL). Thecombined extract was concentrated in vacuo to give a residue which waspurified by silica gel chromatography to afford2-amino-6-(tri-n-butylstannyl)pyrazine (0.5 g)

Precursor 14-69

Preparation of 2-methylsulfonylamino-5-(tri-n-butylstannyl)pyrazine(Example of general procedure Tin-05, below): NaH (60%, 20 mg) was addedinto a solution of 2-amino-5-(tri-n-butylstannyl)pyrazine (0.2 g) in THF(30 mL) at room temperature. After the mixture stirred at roomtemperature for 30 minutes, to it was added methylsulfonyl chloride (63mg). The reaction mixture was stirred at room temperature over 8 hours.The reaction was quenched with aqueous ammonium chloride solution. Theorganic layer was separated, and the aqueous layer was extracted withethyl acetate (3×100 mL). The combined organic extract was dried overmagnesium sulfate, filtered and the filtrate was concentrated in vacuo.The residue was purified by silica gel chromatography to afford2-methylsulfonylamino-5-(tri-n-butylstannyl)pyrazine (20 mg).

Precursors 14-70-14-129

The precursors 14-70-14-129 were prepared according to the followinggeneral procedures designated Tin-01 through Tin-05 (Table 1-3).

General Procedure Tin-01:

To a solution of a base (1.1 equivalents) selected from lithiumdiisopropylamide, 2,2,6,6-tetramethylpiperidinyl lithium, n-butyllithium, sec-butyl lithium or tert-butyl lithium in a solvent selectedfrom tetrahydrofuran, diethyl ether or dimethoxyethane (concentration ofapproximately 0.05 mmol base/mL of solvent) at −78° C. was added anappropriate aryl or heteroaryl substrate (1.0 equivalents) followed byan addition of tri-n-butyltin chloride or trimethyltin chloride (1.1equivalents) in another 2 hours. The reaction was quenched with aqueousammonium chloride solution. The organic layer was separated, and aqueouslayer was extracted with ethyl acetate. The combined organic extract wasdried over magnesium sulfate, filtered and the filtrate concentrated invacuo. The residue was purified by silica gel chromatography to affordthe desired stannane.

General Procedure Tin-02:

To a solution of a base (1.1 equivalents) selected from n-butyl lithium,sec-butyl lithium or tert-butyl lithium in a solvent selected fromtetrahydrofuran, diethyl ether or dimethoxyethane (concentration ofapproximately 0.05 mmol base/mL of solvent) at −78° C. was added anappropriate aryl or heteroaryl bromide or aryl or heteroaryl iodidesubstrate (1.0 equivalents). The reaction mixture was stirred at −78° C.for a period suitable to generate the anion via metal-halogen exchangethen to it was added tri-n-butyltin chloride or trimethyltin chloride(1.1 equivalents). The reaction was quenched with aqueous ammoniumchloride solution. The organic layer was separated, and aqueous layerwas extracted with ethyl acetate. The combined organic extract was driedover magnesium sulfate, filtered and the filtrate concentrated in vacuo.The residue was purified by silica gel chromatography to afford thedesired stannane.

General Procedure Tin-03:

Tri-n-butylstannyl lithium or trimethylstannyl lithium (1.3 equivalents)was prepared at 0° C. in dry solvent selected from THF, diethyl ether ordimethoxyethane (20 mL) from tri-n-butyltin hydride or trimethyltinhydride, respectively (1.3 equivalents) and LDA (lithiumdiisopropylamide, 1.3 equivalents) at a concentration of approximately0.4 mmol of alkylstannyl lithium/mL of solvent. The tri-n-butylstannyllithium or trimethylstannyl lithium solution was then cooled to −78° C.and to it was added an appropriate haloaryl or haloheteroaryl substrate(1.0 equivalent). The reaction mixture was then allowed to warm up toroom temperature over 8 hours. The reaction was then quenched withaqueous ammonium chloride solution. The organic layer was separated, andaqueous layer was extracted with ethyl acetate (3×20 mL). The combinedorganic layer was dried over magnesium sulfate, filtered and thefiltrate concentrated in vacuo. The residue was purified by silica gelchromatography to afford the desired stannane precursor.

General Procedure Tin-04:

To a sealed tube, an appropriate aryl or heteroaryl substrate (1.0equivalent), bis(tri-butyltin) or hexamethylditin (1.0 equivalent) andtetrakis-triphenylphosphine palladium, Pd(Ph₃P)₄ (1.0 mol %) werecombined in dioxane or toluene (10 mL). The reaction was heated at110-120° C. for 10 h. After the mixture cooled down to room temperature,it was poured into water. The solution was extracted with ethyl acetateand the combined extracts were concentrated in vacuo to give a residuewhich was purified by silica gel chromatography to afford the desiredstannane product.

General Procedure Tin-05:

The following general reaction scheme depicts the derivatization ofstannane precursors in which the stannane has a reactive ring NH groupor reactive exocyclic amino, hydroxy or thiol group. The startingstannane is treated with base in an appropriate solvent then is reactedwith suitable electrophiles such as alkyl halides, acid chlorides,sulfonyl chlorides, isocyanates and the like.

An appropriate base selected from sodium hydride, n-butyl lithium,lithium diisopropylamide, potassium carbonate, triethylamine, DBU, DMAPor sodium hexamethyldisilazide (1.0 equivalent) was added into asolution of an appropriate stannane substrate (as depicted above, 1.0equivalent) in an appropriate solvent selected from dichloromethane,THF, diethyl ether or N,N-dimethylformamide at a temperature between−78° C. and room temperature. After the mixture stirred for a periodsufficient to allow deprotonation, typically for 5 to 30 minutes, thento it was added an appropriate electrophile such as an alkyl halide,acid chloride, sulfonyl (1.0 equivalent). The reaction mixture wasstirred, typically at room temperature, over a period of 2 to 8 hours.The reaction was quenched with aqueous ammonium chloride solution. Theorganic layer was separated, and the aqueous layer was extracted withethyl acetate (3×100 mL). The combined organic extract was dried overmagnesium sulfate, filtered and the filtrate was concentrated in vacuo.The residue was purified by silica gel chromatography to afford thedesired stannane precursor.

General Procedure Tin-06

An aryl hilide stannane agent was dissolved in appropriate alcohol,either methanol or ethanol. After a cataylst (pt or pd) was added intothe solvent, the reaction mixture is placed in an environment ofhydrogen under normal or raised pressure. After reaction finishes, thecatalyst is filtered, and, concentration of the mother solution providesa residue which is used in the further reactions without anypurification.

TABLE I-3 Intermed. Starting Method Number Structure Material AppliedIdentification 14-70 

Tin-04 R_(f) = 2.33 min (Column A) ¹H NMR (500 MHz, CDCl3) δ 4.00 (s,6H), 1.63-0.85 (m, 27H) 14-71 

Tin-01 R_(f) = 2.52 min (Column A) ¹H NMR (300 MHz, CDCl₃) δ 7.02 (s,1H), 4.44 (q, 2H, J = 7.02 Hz), 1.63-0.85 (m, 30H) 14-72 

Tin-01 R_(f) = 2.84 min (Column B) ¹H NMR (500 MHz, CDCl3) δ 9.48 (s,1H), 8.45 (s, 1H), 2.03-0.88 (m, 36H) 14-73 

Tin-05 R_(f) = 2.27 min (Column A) ¹H NMR (500 MHz, CDCl₃) δ 7.53 (m,1H), 6.29 (m, 1H), 3.94 (s, 3H), 1.56-0.87 (m, 27H) 14-74 

Tin-05 R_(f) = 2.22 min (Column A) 14-75 

Tin-01 R_(f) = 2.44 min (Column B) ¹H NMR (500 MHz, CDCl₃) δ 8.89 (s,1H), 8.34 (s, 1H), 1.61-0.85 (m, 27H) 14-76 

Tin-01 R_(f) = 3.41 min (Column A, flow rate = 4 ml/min) ¹H NMR (300MHz, CDCl3) δ 8.58 (d, 1H, J = 2.52 Hz), 8.13 (d, 1H, J = 2.52 Hz),1.63-0.85 (m, 27H) 14-77 

Tin-01 R_(f) = 3.89 min (Column A, flow rate = 4 ml/min) ¹H NMR (300MHz, CDCl3) δ 8.63 (s, 1H), 1.61-0.85 (m, 27H) 14-78 

Tin-01 R_(f) = 3.86 min (Column A, flow rate = 4 ml/min) ¹H NMR (300MHz, CDCl3) δ 8.24 (s, 1H), 1.61-0.85 (m, 27H) 14-79 

Tin-04 R_(f) = 2.10 min (Column B) ¹H NMR (500 MHz, CDCl3) δ 7.90 (s,1H), 7.26 (s, 1H), 1.58-0.87 (m, 27H) 14-80 

Tin-04 R_(f) = 1.83 min (Column A) 14-81 

Tin-04 R_(f) = 1.84 min (Column A) 14-82 

Tin-04 R_(f) = 1.84 min (Column A) 14-83 

Tin-04 R_(f) = 1.90 min (Column A) 14-84 

Tin-01 R_(f) = 2.23 min (Column A) 14-85 

Tin-04 R_(f) = 1.92 min (Column A) 14-86 

Tin-03 R_(f) = 2.01 min (Column A) 14-87 

Tin-01 R_(f) = 2.45 min (Column A) 14-88 

Tin-01 R_(f) = 2.67 min (Column C) 14-89 

Tin-01 R_(f) = 2.31 min (Column C) 14-90 

Tin-04 R_(f) = 2.71 min (Column D) 14-91 

Tin-01 R_(f) = 2.49 min (Column C) 14-92 

Tin-01 R_(f) = 2.42 min (Column C) 14-93 

Tin-01 R_(f) = 3.49 min (Column C) Flow Rate = 4 ml/min 14-94 

Tin-01 R_(f) = 2.46 min (Column C) 14-95 

Tin-05 Rf = 2.15 min (Column A) 14-96 

Tin-01 R_(f) = 2.28 min (Column C) 14-97 

Tin-01 R_(f) = 2.60 min (Column C) 14-98 

Tin-01 R_(f) = 2.37 min (Column A) 14-99 

Tin-01 R_(f) = 2.59 min (Column A) 14-100

Tin-01 R_(f) = 2.49 min (Column C) 14-101

Tin-04 R_(f) = 2.41 min (Column A) 14-102

Tin-04 R_(f) = 1.88 min (Column E) 14-103

Tin-04 R_(f) = 1.92 min (Column E) 14-104

Tin-04 R_(f) = 2.01 min (Column E) 14-105

Tin-04 R_(f) = 2.15 min (Column E) 14-106

Tin-04 R_(f) = 1.91 min (Column E) 14-107

Tin-04 Rf = 1.95 min (Column A) 14-108

Tin-04 Rf = 1.93 min (Column A) 12-109

Tin-01 Rf = 1.95 min (Column A) 14-110

Tin-01 Rf = 1.83 min (Column A) ¹H NMR (500 MHz, CDCl3) δ 9.03 (d, 1H, J= 5.15 Hz), 7.49 (d, 1H, J = 7.95 Hz), 7.26 (m, 1H), 1.61-0.86 (m, 27H);¹³C NMR (125 MHz, CDCl3) δ 175.3, 149.8, 133.2, 123.7, 29.0, 27.3, 13.6,10.1. 14-111

Tin-01 R_(f) = 2.18 min (Column E) ¹H NMR (500 MHz, CDCl3) δ 9.22 (s,1H), 8.46 (d, 1H, J = 4.80 Hz), 7.42 (d, 1H, J = 4.75 Hz), 1.56-0.86 (m,27H); ¹³C NMR (125 MHz, CDCl3) δ 185.4, 158.0, 153.2, 130.6, 28.9, 27.2,13.5, 9.9. 14-112

Tin-04 Rf = 1.96 min (Column A) 14-113

Tin-01 Rf = 2.61 min (Column A) 14-114

Tin-01 Rf = 2.85 min (Column A) 14-115

Tin-05 Rf = 2.09 min (Column A) ¹H NMR (500 MHz, CDCl₃) δ 8.12 (s, 1H),7.95 (s, 1H), 4.11 (s, 1H), 2.95 (s, 3H), 2.03-0.85 (m, 27H) 14-116

Tin-05 Rf = 2.16 min (Column A) ¹H NMR (500 MHz, CDCl₃) δ 8.08 (s, 1H),7.92 (s, 1H), 4.49 (s, 1H), 3.35 (m, 2H), 1.63-0.85 (m, 30H) 14-117

Tin-04 Rf = 2.19 min (Column A) 14-118

Tin-04 Rf = 2.18 min (Column A) 14-119

Tin-04 Rf = 2.47 min (Column A) ¹H NMR (500 MHz, CDCl3) δ 7.85 (s, 1H),4.91 (s, 2H), 2.16-0.87 (m, 27H) 14-120

Tin-04 Rf = 2.61 min (Column A) 14-121

Tin-04 Rf = 2.92 min (Column A) 14-122

Tin-04 Rf = 1.93 min (Column A) 14-123

Tin-01 Rf = 2.20 min (Column A) 14-124

Tin-01 Rf = 2.50 min (Column A) ¹H NMR (500 MHz, CDCl3) δ 9.07 (s, 1H),7.87 (s, 1H), 1.59-0.85 (m, 27H) 12-125

Tin-04 Rf = 1.97 min (Column A) 14-126

Tin-04 Rf = 1.97 min (Column A) 14-127

Tin-01 Rf = 2.70 min (Column E) ¹H NMR (500 MHz, CDCl3) δ 8.11 (d, 1H, J= 5.2 Hz), 7.41 (d, 1H, J = 5.2 Hz), 6.94 (s, 1H), 1.62-0.89 (m, 27H)14-128

Tin-06 ¹H NMR (500 MHz CDCl3) δ 8.12 (d, 1H, J = 5.2 Hz), 7.78 (s, 1H),7.46 (d, 1H, J = 5.2 Hz), 6.84 (s, 1H), 1.98-0.85 (m, 27H) 14-129

Tin-01 Rf = 1.86 min (Column A) R_(f) = retention time

The following Table 1-4 contains novel stannane reagents which can beprepared by the methodology described above and then could be used toprepare compounds of formula I.

TABLE I-4 Precursor Number Structure Reference

From 5-iodo2-chloro-1, 3 pyrimidine. Fluoropyrimidines are obtained byfluorination of chloropyrimidines with CsF in N-methy1-2-pyrrolidinoneor DMF 2.5-63 h at 80-150° C. The iodo is then converted to the lithiumreagent with tBuLi and trapped with Bu3SnCl. See Sandosham above.

Turck, A.; et.al Lab.. J. Organomet. Chem. (1991), 412(3),301-10.Metallation of 2,6-dicloropyrazine and quench with Bu3SnCl

Analogous to Lehn, L. M., et al. Chem. Eur. J. 2000, 6, 4133.

Metallation of 1-trityl-4-iodo imidazole (prepared in Takahashi,Kazuyuki; Kirk, Kenneth L.; Cohen, Louis A. Lab. Chem., Natl. Inst.Arthritis Diabetes Dig. Kidney Dis., Bethesda, MD, USA. J. LabelledCompd. Radiopharm. (1986), 23(1), 1-8) using tBuLi in THF at −78 andquenching with Bu₃SnCl. Detritylate with TFA or aqHCl after coupling toazaindole core.

Metallation of 1-methyl-4- iodo imidazole (prepared in Takahashi,Kazuyuki; Kirk, Kenneth L.; Cohen, Louis A. Lab. Chem., Natl. Inst.Arthritis Diabetes Dig. Kidney Dis., Bethesda, MD, USA. J. LabelledCompd. Radiopharm. (1986), 23(1), 1-8) using tBuLi in THF at −78 andquenching with Bu₃SnCl. El Borai, M.; Moustafa, A.H.; Anwar, M.; AbdelHay, F. I. The bromo derivative is described in Pol. J. Chem. (1981), 55(7-8), 1659-65 and can be used to generate the tin reagent viatransmetallation.

4,5difluoroimidazole prepared as in Dolensky, Bohumil; et. al, USA. J.Fluorine Chem. (2001), 107(1), 147-148.

Dolensky, Bohumil; et. al, USA. J. Fluorine Chem. (2001), 107(1),147-148.

Select General Procedures, Via S_(N)Ar Reactions, for the Preparation ofStarting Materials for Tin Agents

a. Preparation of 2-bromo-5-substituted-pyrazine,5-bromo-2-subsituted-thiazole, 2-substituted-thiazaole,4-chloro-6-substituted-pyrimidine and 5-bromo-2-substituted-pyrimidine

To a flask, an appropriate pyrazine, pyrimidine or thiazole (1.0equivalent) and a nucleophile (Nu), such as amine, alcohol orthio-derivatives in one equivalence or an exess amount were combined ina solvent such as THF, DMF or alcohol, with or without an addition ofNaH. The reaction was either stirred at room temperature or underheating for one to three days. After all the solvents were removed, theresidue was partitioned between saturated NaHCO₃ and EtOAc. The aqueouslayer was extracted with ethyl acetate and the combined extracts wereconcentrated in vacuo to give a residue, which was purified by silicagel chromatography to afford the desired product.

MS MS Starting Reaction Rf (M + H)+ (M + H)+ Material Product Condition(minutes) Cald. Obsv.

  SM-01

SM-01 (2 g) Piperazine (10 g), THF (50 ml), r.t. 0.56 (column G) 243.02243.03

  SM-01

SM-01 (1 g), MeNH₂ (2M in THF, 100 ml), r.t. 0.89 (column E) 187.93187.98

  SM-01

SM-01 (1 g), Me₂NH (2M in THF, 100 ml), r.t. 1.19 (column E) 201.92202.00

  SM-01

SM-01 (1 g), MeONa (0.5M in MeOH, 100 ml), r.t. 1.05 (column E) 188.91188.97

  SM-01

SM-01 (50 mg), NaH (17 mg), 2-amino-1,3,4- thiadiazole (25 mg), DMF 5ml) r.t. 1.21 (column E) 257.94 257.89

  SM-01

SM-01 (50 mg), NaH (17 mg), N- benzylpiperazine (25 mg), DMF 5 ml) r.t.1.04 (column E) 333.07 332.99

  SM-01

SM-01 (50 mg), NaH (17 mg), N,N- diethylamino- ethanol (0.033 ml), DMF 5ml) r.t. 0.72 (column E) 274.06 273.97

  SM-02

SM-02 (2 g) Piperazine (10 g), THF (50 ml), r.t. 0.89 (column E) 247.99247.97

  SM-02

SM-05 (1 g), Me₂NH (2M in THF, 100 ml), r.t. 0.65 (column E) 206.89206.96

  SM-02

SM-02 (1 g), MeONa (0.5M in MeOH, 100 ml), r.t. 1.35 (column E) 193.93193.84

  SM-02

SM-03 (50 mg), NaH (16 mg), imidiazole (77 mg), DMF 5 ml) r.t. 0.89(column E) 229.94 229.83

  SM-02

SM-02 (50 mg), NaH (16 mg), N- benzylpiperazine (30 mg), DMF 5 ml) r.t.1.02 (column E) 338.03 337.98

  SM-02

SM-02 (50 mg), NaH (16 mg), N,N- diethylamino- ethanol (0.033 ml), DMF 5ml) r.t. 0.83 (column E) 279.02 278.95

  SM-03

SM-03 (50 mg), NaH (25 mg), imidazole (25 mg), DMF 5 ml) r.t. 0.31(column E) 151.91 152.03

  SM-03

SM-03 (50 mg), NaH (25 mg), N- benzylpiperazine (37 mg), DMF 5 ml) r.t.0.66 (column E) 260.07 260.12

  SM-03

SM-03 (50 mg), NaH (25 mg), N,N- diethylamino- ethanol (0.05 ml), DMF 5ml) r.t. 0.46 (column E) 201.11 201.02

  SM-04

SM-04 (1 g), MeONa (0.5M in MeOH, 13.52 ml), r.t. 0.86 (column E) 145.02144.99

  SM-04

SM-04 (1 g), MeNH₂ (2M in THF, 100 ml), r.t. 0.46 (column E), 144.03143.96

  SM-05

SM-05 (1 g), MeONa (0.5M in MeOH, 100 ml), 1 day, r.t. 0.91 (column E)188.97 188.91

  SM-05

SM-05 (1 g), MeNH₂ (2M in THF, 100 ml), r.t. 0.84 (column E) 187.99187.94

  SM-05

SM-05 (1 g), Me₂NH (2M in THF, 100 ml), r.t. 1.24 (column E) 202.00201.98

b. Preparation of 2-bromo-5,6-disubstituted-pyrazine

Step One

To a flask, an appropriate pyrazine (1.0 equivalent) and a nucleophile,such as amine or sodium alkoxide in an exess amount were combined in asolvent such as water or THF or without solvent. The reaction was eitherstirred at room temperature or under heating for one to three days.After all the solvents were removed, a residue was collected and used inthe further steps without any purification.

MS MS Starting Reaction Rf (M + H)+ (M + H)+ Material Product Condition(minutes) Cald. Obsv.

  SM-06

SM-06 (100 mg), propylamine (2 ml), r.t. 1.28 (column C) 172.06 172.09

  SM-06

SM-06 (100 mg), Me₂NH (2M in THF, 10 ml) or Me₂NH (40% in water, 10 ml),r.t. 1.21 (column C) 158.05 158.07

  SM-06

SM-06 (100 mg), Me2NH (40% in water, 10 ml), 100° C. 0.49 (column C)167.13 167.19

  SM-06

SM-06 (100 mg), MeNH₂ (2M in THF, 10 ml), r.t. 0.72 (column C) 144.03144.07

  SM-06

SM-06 (100 mg), NH₄OH (10 ml), 100° C. 0.41 (column C) 162.04 (M +MeOH + H)⁺ 162.06 (M + MeOH + H)⁺

Step Two

To a flask, the crude pyrazine derivative obtained from the step one(1.0 equivalent) and a nucleophile, such as amine or sodium alkoxide inan excess amount were combined in a solvent such as water or THF orwithout solvent. The reaction was either stirred at room temperature orunder heating for one to three days. After all the solvents wereremoved, a residue was collected and used in the further steps withoutany purification.

MS MS Starting Reaction Rf (M + H)+ (M + H)+ Material Product Condition(minutes) Cald. Obsv.

  SM-07

SM-07 (2 g), MeONa (12.5 wt %, 100 ml, 100° C. 0.28 (column C) 140.08140.14

  SM-08

SM-08 (2 g), MeONa (12.5 wt %, 20 ml), 100° C. 0.28 (column C) 158.13158.09

  SM-07

SM-07 (2 g), MeNH₂ (40% in water, 100 ml), 100° C. 0.34 (column C)139.10 139.13

Step Three

To a flask, the crude pyrazine derivative obtained from the step two(1.0 equivalent) was dissolved in methylene chloride. A slightly excessof bromine was then added into the mixed solution. The reaction wasstirred at room temperature for ten hours. After all the solvents wereremoved, a residue was collected and purified by silica gelchromatography to afford the desired product.

MS MS Starting Reaction Rf (M + H)+ (M + H)+ Material Product Condition(minutes) Cald. Obsv.

  SM-09

SM-09 (5 g), bromine (1.34 ml), CH₂Cl₂ (100 ml) 1.77 (column C) 249.97250.02

  SM-10

SM-10 (2 g), bromine (0.72 ml), CH₂Cl₂ (20 ml) 1.13 (column C) 217.99217.98

  SM-11

SM-11 (2 g), bromine (0.72 ml), CH₂Cl₂ (20 ml) 0.98 (column C) 203.98203.99

General Procedure of the Preparation of 2-Alkyl-5-Bromo-Pyrimide:

To a sealed tube, 5-bromo-2-iodopyrimidine (1.0 equivalent),tri-alkylalumimun (1.5 equivalent) and tetrakis-triphenylphosphinepalladium, Pd(Ph₃P)₄ (1.0 mol %) were combined in dioxane (10 mL). Thereaction was heated at 110-120° C. for 10 h. After the mixture cooleddown to room temperature, it was poured into water. The solution wasextracted with ethyl acetate and the combined extracts were concentratedin vacuo to give a residue which was purified by silica gelchromatography to afford the desired 2-alkyl-5-bromopyrimidine product.

MS MS Rf (M + H)+ (M + H)+ R3Al Product (minutes) Cald. Obsv. Me₃Al

0.90 (column E) 172.94 172.97 (i-Bu)₃Al

1.45 (column E) 215.02 214.99Prep of triazine stannane for Stille coupling to prepare examples ofclaim 1. (the sulfur can then be removed with Raney Nickel to giveadditional desulfurized triazines).

2,2,6,6-tetramethylpiperidine (2.0 ml, 11.81 mmol) in 30 ml of THF wascooled to −78° C. and treated with n-butyllithium (4.7 ml, 11.81 mmol,2.5M in hexane). After stirring 30 min at 0° C., the reaction was cooledto −78° C. again and 3-methylthio-1,2,4-triazine (1.0 g, 7.87 mmol) wasadded. The resulting solution was stirred at −78° C. for 30 min beforetributyltin chloride (2.1 ml, 7.87 mmol) was added. The reaction waskept at −78° C. for 1 hr, then quenched with water. The THF solvent wasremoved on rotarory evaporator and the remaining solution was extractedwith ethylacetate. The organic layer was dried over MgSO4, filtered andthe filtrate was concentrated. The residue was chromatographed to afford96 mg of 3-methylthio-6-tributyltin-1,2,4-triazine.

1H NMR (300 Hz, CHCl3): 8.83 (s, 1H); 2.62 (s, 3H); 2.04-0.79 (m, 27H).LC/MS: (ES+) M/Z (M+H)+=418, RT=2.29 min.

Precursor 13a

To a mixture of 5q (50 mg, 105 μmol) and Pd(PPh₃)₄ (25 mg, 21 μmol) wasadded 1,4-dioxane (1 ml) and vinyl tributylstannane (50 mg, 158 μmol).The reaction mixture was heated in a sealed tube at 145° C. for 3 hours.After cooling to ambient temperature, the reaction mixture was addedMeOH (4 ml) and then filtered. The filtrate was purified by preparativereverse phase HPLC to give the TFA salt of Precursor 13a using themethod: Start % B=30, Final % B=75, Gradient time=20 min, Flow Rate=25ml/min, Column: YMC C18 5 um 20×100 mm, Fraction Collection: 7.92-8.58min. ¹H NMR: (CD₃OD) δ 8.61 (s, 1H), 8.37 (s, 1H), 7.47 (b s, 5H), 7.31(dd, J=17.3, 11.3, 1H), 6.50 (d, J=17.3, 1H), 5.97 (d, J=11.3, 1H),3.97-3.38 (b m, 8H); LC/MS: (ES+) m/z (M+H)⁺ =423, 425; HPLCR_(t)=1.887.

Precursor 14

To a mixture of precursor 5q (30 mg, 63 μmol) and Pd(PPh₃)₄ (20 mg, 17μmol) was added 1,4-dioxane (1 ml) and 1-tributylstannyl propyne (40 mg,122 μmol). The reaction mixture was heated in a sealed tube at 145° C.for 2 hours. After cooling to ambient temperature, the reaction mixturewas added MeOH (4 ml) and then filtered. The filtrate was purified bypreparative reverse phase HPLC to give the TFA salt of precursor 14(1-(4-Benzoyl-piperazin-1-yl)-2-(4-chloro-7-prop-1-ynyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-ethane-1,2-dione)using the method: Start % B=20, Final % B=80, Gradient time=20 min, FlowRate=25 ml/min, Column: YMC C18 Sum 20×100 mm, Fraction Collection:8.74-9.00 min. ¹H NMR: (CD₃OD) δ 8.47 (s, 1H), 8.27 (s, 1H), 7.46 (b s,5H), 3.82-3.34 (b m, 8H), 2.26 (s, 3H); LC/MS: (ES+) m/z (M+H)⁺ =435,437; HPLC (alternate conditions B, column G) R_(t)=2.123.

Precursor 15

To a solution of precursor 5q (50 mg, 0.11 mmol) in DMF (1 ml) was addedCuCN (30 mg, 0.335 mmol). The reaction mixture was heated at 170° C. for30 min. After cooling to ambient temperature, the reaction mixture wasdiluted with MeOH (15 ml), filtered under gravity, and the filtrateevaporated in vacuo to afforded a brownish residue. To the residue inEtOH (3 ml) at ambient temperature was bubbled hydrogen chloride gas for10 minutes to give a yellow solution, which was purified by preparativereverse phase HPLC using the method: Start % B=15, Final % B=85,Gradient time=15 min, Flow Rate=40 ml/min, Column: XTERRA C18 5 um30×100 mm, Fraction Collection: 10.40-10.85 min; ¹H NMR: (CD₃OD) 8.35(s, 1H), 8.33 (s, 1H), 7.42 (b s, 5H), 3.95-3.41 (b m, 8H); LC/MS: (ES+)m/z (M+H)⁺ =440, 442; HPLC (alternate conditions B, column G)R_(t)=1.820.

Precursor 16

Preparation of Precursor 16:

To a suspension of precursor 15 (6 mg, 13 mol) in a mixture of AcOH (0.5ml) and Ac₂O (1.0 ml) at 0° C. was charged with sodium nitrite (17 mg,246 mol). The reaction mixture was stirred at 0° C. for 30 min. and thenat ambient temperature for 1 hour. After addition of MeOH (4 ml), thereaction mixture was purified by preparative reverse phase HPLC to givethe TFA solvate of the title compound using the method: Start % B=15,Final % B=80, Gradient time=15 min, Flow Rate=25 ml/min, Column: YMC C185 um 20×100 mm, Fraction Collection: 9.48-10.03 min. ¹H NMR: (DMSO-d₆) δ12.76 (s, 1H), 8.48 (s, 1H), 8.32 (d, J=3.0, 1H), 7.44 (b s, 5H),3.97-3.47 (b m, overlapping with water peak, 8H); LC/MS: (ES+) m/z(M+H)⁺ =441, 443; HPLC (alternate conditions B, column G) R_(t)=1.530.Ref: Amide hydrolysis: Evans, D. A.; Carter, P. H.; Dinsmore, C. J.;Barrow, J. C.; Katz, J. L.; Kung, D. W. Tetrahedron Lett. 1997, 38, 4535and references cited therein.

Additional Piperazine Precursors

N-(Benzoyl)-2-methylpiperazine, Precursor 17a, was prepared according tothe procedure described in Ref 90(b). ¹H NMR (300 MHz, CD₃OD) δ7.47 (m,5H), 3.30-2.70 (m, 7H), 1.36 (d, 3H, J=6.90 Hz); ¹³C NMR (75 MHz, CD₃OD)δ171.0, 135.4, 129.7, 128.5, 126.3, 48.5, 44.3, 14.5;² HRMS m/z: (M+H)⁺calcd for C₁₂H₁₂N₂O 205.1341. found 205.1341. ²Some carbon peaks aremissing due to the overlap of signals.

(R)—N-(Benzoyl)-2-methylpiperazine, Precursor 17b, was preparedaccording to the procedure described in Ref 90(b). ¹H NMR (300 MHz,CD₃OD) δ7.41 (m, 5H), 3.31-2.70 (m, 7H), 1.35 (d, 3H, J=6.90 Hz). MSm/z: (M+H)⁺ Calc'd for C₁₂H₁₇N₂O: 205.13. Found 205.16. HPLC retentiontime: 0.51 minutes (column L).

(S)—N-(Benzoyl)-2-methylpiperazine, Precursor 17c, was preparedaccording to the procedure described in Ref 90(b). ¹H NMR (300 MHz,CD₃OD) δ7.41 (m, 5H), 3.31-2.72 (m, 7H), 1.35 (d, 3H, J=6.90 Hz). MSm/z: (M+H)⁺ Calc'd for C₁₂H₁₇N₂O: 205.13. Found 205.16. HPLC retentiontime: 0.50 minutes (column L).

N-(Benzoyl)-2-ethylpiperazine, Precursor 17d, was prepared according tothe procedure described in Ref. 90(b). ¹H NMR (300 MHz, CD₃OD) δ7.49 (m,5H), 3.34-2.80 (m, 7H), 2.10-1.70 (m, 2H), 0.85 (b, 3H); ¹³C NMR (75MHz, CD₃OD) δ171.5, 135.1, 129.8, 128.5, 126.5, 48.5, 46.0, 43.9, 21.8,9.6;² HRMS m/z: (M+H)⁺ calcd for C₁₃H₁₉N₂O 219.1497. found 219.1501.²Some carbon peaks are missing due to the overlap of signals.

Preparation of Compounds of Formula I Example 1

Typical Procedure for Coupling Azaindole with Aromatic Boron Reagent (anExample of the General Procedure Described Below for Examples 2-14):

Preparation of1-benzoyl-3-(R)-methyl-4-[(7-(4-fluorophenyl)-6-azaindol-3-yl)-oxoacetyl]-piperazineis an example of Step E as described in Scheme 15. To a sealed tube,1-(benzoyl)-3-(R)-methyl-4-[(7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine,Precursor 5a, (20 mg, 0.049 mmol), 4-fluorophenylboronic acid, Precursor14a-9, (8.2 mg, 0.059 mmol), Pd(Ph₃P)₄ (5 mg) and K₂CO₃ (20 mg, 0.14mmol) were combined in 1.5 mL of DMF and 1.5 mL of water. The reactionwas heated at 110-120° C. for 10 h. After the mixture cooled down to rt,it was poured into 20 mL of water. The solution was extracted with EtOAc(4×20 mL). The combined extract was concentrated to give a residue whichwas purified using a Shimadzu automated preparative HPLC System to givecompound1-benzoyl-3-(R)-methyl-4-[(7-(4-fluorophenyl)-6-azaindol-3-yl)-oxoacetyl]piperazine(1.8 mg, 7.9%). MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₄FN₄O₃: 471.18. found471.08. HPLC retention time: 1.12 minutes (column A).

Examples 2-14

Examples 2-14 were prepared according to the following general method ina manner analogous to the preparation of Example 1.

Typical Procedure for Coupling Azaindole with Aromatic Boron Reagent:

To a sealed tube, an appropriately substituted azaindole precursor(0.049 mmol), an appropriate boronic acid derivative (0.059 mmol),Pd(Ph₃P)₄ (5 mg) and K₂CO₃ (20 mg, 0.14 mmol) were combined in 1.5 mL ofDMF and 1.5 mL of water. The reaction was heated at 110-120° C. for 10h. After the mixture cooled down to rt, it was poured into 20 mL ofwater. The solution was extracted with EtOAc (4×20 mL). The combinedextract was concentrated in vacuo to give a residue which was purifiedusing a Shimadzu automated preparative HPLC System to provide thedesired compound.

Example 2

Example 2, was prepared according to the general method described abovestarting from Precursor 5g and 4-chlorophenyl boronic acid, Precursor14a-10, to provide1-benzoyl-4-[(7-(4-chlorophenyl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₄FN₄O₃: 473.14. found 473.13. HPLCretention time: 1.43 minutes (column B).

Example 3

Example 3, was prepared according to the general method described abovestarting from Precursor 5a and 3-amino-4-methylphenyl boronic acid,Precursor 14a-11, to provide1-benzoyl-3-®-methyl-4-[(7-(3-amino-4-methylphenyl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₄ClN₄O₃: 482.22. found 482.25. HPLCretention time: 1.35 minutes (column B).

Example 4

Example 4, was prepared according to the general method described abovestarting from Precursor 5g and 4-hydroxycarbonylphenyl boronic acid,Precursor 14a-12, to provide1-benzoyl-4-[(7-(4-carboxy-phenyl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₄ClN₄O₃: 483.17. found 483.10. HPLCretention time: 1.00 minutes (column A).

Example 5

Example 5, was prepared according to the general method described abovefrom1-benzoyl-3-methyl-4-[(7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazineand 3,4-methylenedioxyphenyl boronic acid, Precursor 14a-13, to provide1-benzoyl-3-methyl-4-[(7-(3,4-methylenedioxyphenyl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₅N₄O₅: 497.18. found 497.03. HPLCretention time: 1.41 minutes (column B).

Example 6

Example 6, was prepared according to the general method described abovestarting from Precursor 5a and furan-2-yl boronic acid to provide1-benzoyl-3-®-methyl-4-[(7-(furan-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₄O₄: 443.17. found 443.12. HPLCretention time: 1.20 minutes (column A).

Example 7

Example 7, was prepared according to the general method described abovestarting from Precursor 5g and furan-2-yl boronic acid to provide1-benzoyl-4-[(7-(furan-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine MSm/z: (M+H)⁺ Calc'd for C₂₄H₂₁N₄O₄: 429.16. found 428.98. HPLC retentiontime: 1.36 minutes (column A).

Example 8

Example 8, was prepared according to the general method described abovestarting from Precursor 5g and benzofuran-2-yl boronic acid to provide1-benzoyl-4-[(7-(benzofuran-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazineMS m/z: (M+H)⁺ Calc'd for C₂₈H₂₃N₄O₄: 479.17. found 479.09. HPLCretention time: 1.67 minutes (column B).

Example 9

Example 9, was prepared according to the general method described abovestarting from Precursor 5a and thien-2-yl boronic acid to provide1-(benzoyl)-3-®-methyl-4-[(7-(thien-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazineMS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₄O₃S: 459.15. found 459.10. HPLCretention time: 1.20 minutes (column A).

Example 10

Example 10, was prepared according to the general method described abovestarting from Precursor 5g and pyridin-4-yl boronic acid to provide1-(benzoyl)-4-[(7-(pyridin-4-yl)-6-azaindol-3-yl)-oxoacetyl]piperazineMS m/z: (M+H)⁺ Calc'd for C₂₅H₂₂N₅O₃: 440.17. found 440.10. HPLCretention time: 0.97 minutes (column A).

Example 11

Example 11, was prepared according to the general method described abovestarting from Precursor 5g and quinolin-8-yl boronic acid, Precursor14a-14, to provide1-benzoyl-4-[(7-(quinolin-8-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine MSm/z: (M+H)⁺ Calc'd for C₂₅H₂₂N₅O₃: 490.19. found 490.09. HPLC retentiontime: 1.34 minutes (column B).

Example 12

Example 12, was prepared according to the general method described abovestarting from Precursor 5a and 2,4-dimethoxypyrimidin-5-yl boronic acid,Precursor 14a-4, to provide1-benzoyl-3-®-methyl-4-[(7-(2,4-dimethoxy-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazineMS m/z: (M+H)⁺ Calc'd for C₂₂H₂₂N₆O₅: 515.20. found 515.28. HPLCretention time: 1.17 minutes (column B).

Example 13

Example 13, was prepared according to the general method described abovestarting from Precursor 5b and 2,4-dimethoxypyrimidin-5-yl boronic acid,Precursor 14a-4, to provide1-benzoyl-4-[(4-methoxy-7-(2,4-dimethoxy-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine¹H NMR (500 MHz, CD₃OD) δ 8.71 (s, 1H), 8.64 (s, 1H), 8.21 (s, 1H), 7.48(s, 5H), 4.15 (s, 3H), 4.13 (s, 3H), 3.84 (s, 3H), 3.64-3.34 (m, 8H). MSm/z: (M+H)⁺ Calc'd for C₂₉H₃₅N₆O₆: 531.20. found 531.26. HPLC retentiontime: 1.09 minutes (column A).

Example 14

Example 14, was prepared according to the general method described abovestarting from Precursor 5b and pyridin-4-yl boronic acid to provide1-benzoyl-4-[(4-methoxy-7-(pyridin-4-yl)-6-azaindol-3-yl)-oxoacetyl]piperazineMS m/z: (M+H)⁺ Calc'd for C₂₆H₂₄N₅O₄: 470.18. found 470.32. HPLCretention time: 1.02 minutes (column A).

Example 15

Typical Procedure for Coupling Azaindole with Aromatic Tin Reagent (anExample of the General Procedure Described Below for Examples 16-53):

Preparation of Example 15,1-benzoyl-4-[(4-methoxy-7-(2-(1,1-dimethylethylaminocarbonyl)-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazineis an example of Step E as described in Scheme 15. To a sealed tube,1-benzoyl-4-[(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetyl]piperazine,Precursor 5b, (20 mg),2-(1,1-dimethylethylaminocarbonyl)-5-tributylstannyl-pyrazine (1.2equivalents, 27 mg.) and Pd(Ph₃P)₄ (1 mg) were combined in 1.5 mL ofdioxane. The reaction was heated at 110-120° C. for 10 h. After themixture cooled down to room temperature, it was poured into 5 mL ofwater. The solution was extracted with EtOAc (4×5 mL). The combinedextract was concentrated in vacuo to give a residue which was purifiedusing a Shimadzu automated preparative HPLC System to give compound1-benzoyl-4-[(4-methoxy-7-(2-(1,1-dimethylethylaminocarbonyl)-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine(1 mg); MS m/z: (M+H)⁺ Calc'd for C₃₀H₃₂N₇O₅: 570.25. found 570.43. HPLCretention time: 1.83 minutes (column B).

Examples 16-54

Examples 16-54 were prepared according to the following generalprocedure by a method analogous to the method described for thepreparation of Example 15.

Typical Procedure for Coupling Azaindole with Aromatic Tin Reagent:

To a sealed tube, an appropriate azaindole (0.049 mmol), an appropriatestannane (0.059 mmol) and Pd(Ph₃P)₄ (1 mg) were combined in 1.5 mL ofdioxane. The reaction was heated at 110-120° C. for 10 h. After themixture cooled down to rt, it was poured into 5 mL of water. Thesolution was extracted with EtOAc (4×5 mL). The combined extract wasconcentrated to give a residue which was purified using a Shimadzuautomated preparative HPLC System to provide the desired compound.

Example 16

Example 16, was prepared according to the general method described abovestarting from Precursor 5a and pyrimidin-5-yl tributyltin, Precursor14-9, to provide1-benzoyl-3-(R)-methyl-4-[(7-(pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₆O₃: 455.18. found 455.17. HPLCretention time: 1.33 minutes (column B).

Example 17

Example 17, was prepared according to the general method described abovestarting from Precursor 5g and pyrimidin-5-yl tributyltin, Precursor14-9, to provide1-benzoyl-4-[(7-(pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazineMS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₆O₃: 441.17. found 441.07. HPLCretention time: 1.30 minutes (column B).

Example 18

Example 18, was prepared according to the general method described abovestarting from Precursor 5a and pyridin-3-yl tributyltin, Precursor14a-2, to provide1-benzoyl-3-(R)-methyl-4-[(7-(pyridin-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazineMS m/z: (M+H)⁺ Calc'd for C₂₆H₂₄N₅O₃: 454.19. found 454.17. HPLCretention time: 1.11 minutes (column A).

Example 19

Example 19, was prepared according to the general method described abovestarting from Precursor 5g and pyridin-2-yl tributyltin, Precursor14a-19, to provide1-benzoyl-4-[(7-(pyridin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine MSm/z: (M+H)⁺ Calc'd for C₂₅H₂₂N₅O₃: 440.17. found 440.07. HPLC retentiontime: 1.40 minutes (column B).

Example 20

Example 20, was prepared according to the general method described abovestarting from Precursor 5a and thiazol-2-yl tributyltin, Precursor14a-21, to provide1-benzoyl-3-(R)-methyl-4-[(7-(thiazol-2-yl)-6-azaindol-3-yl)oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₂N₅O₃S: 460.14. found 460.15. HPLCretention time: 1.48 minutes (column B).

Example 21

Example 21, was prepared according to the general method described abovestarting from Precursor 5g and thiazol-2-yl tributyltin, Precursor14a-21, to provide1-benzoyl-4-[(7-(thiazol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MSm/z: (M+H)⁺ Calc'd for C₂₃H₂₀N₅O₃S: 446.13. found 446.03. HPLC retentiontime: 1.44 minutes (column B).

Example 22

Example 22, was prepared according to the general method described abovestarting from Precursor 5b and 1-methylpyrazol-3-yltributyltin, toprovide1-benzoyl-4-[(4-methoxy-7-(1-methyl-pyrazol-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₅N₆O₄: 473.19. found 473.28. HPLCretention time: 1.18 minutes (column B).

Example 23

Example 23, was prepared according to the general method described abovestarting from Precursor 5b and Intermediate 14-9 to provide1-benzoyl-4-[(4-methoxy-7-(pyridazin-4-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₆O₄: 471.18. found 471.26. HPLCretention time: 1.20 minutes (column B).

Example 24

Example 24, was prepared according to the general method described abovestarting from Precursor 5b and 2-aminopyrimidin-5-yl tributyltin, toprovide1-benzoyl-4-[(4-methoxy-7-(2-amino-pyrimidin-5-yl))-6-azaindol-3-yl)-oxoacetyl]piperazineMS m/z: (M+H)⁺ Calc'd for for C₂₅H₂₄N₇O₄: 486.19. found 486.24. HPLCretention time: 1.19 minutes (column A).

Example 25

Example 25, was prepared according to the general method described abovestarting from Precursor 5b and pyridin-3-yl tributyltin, Precursor14a-2, to provide1-benzoyl-4-[(4-methoxy-7-(pyridin-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₄N₅O₄: 470.18. found 470.19. HPLCretention time: 1.04 minutes (column A).

Example 26

Example 26, was prepared according to the general method described abovestarting from Precursor 5b and 2-aminopyrazin-5-yl trimethyltin,Precursor 14-28, to provide1-benzoyl-4-[(4-methoxy-7-(2-amino-pyrazin-5-yl))-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₄N₇O₄: 486.19. found 470.19. HPLCretention time: 1.13 minutes (column B).

Example 27

Example 27, was prepared according to the general method described abovestarting from Precursor 5b and 1-methylimidazol-2-yl trimethyltin,Precursor 14-5, to provide1-benzoyl-4-[(4-methoxy-7-(1-methyl-imidazol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₅N₆O₄: 473.18. found 473.27. HPLCretention time: 1.07 minutes (column B).

Example 28

Example 28, was prepared according to the general method described abovestarting from Precursor 5b and 1-methylpyrrol-2-yltributyltin, Precursor14a-15, to provide1-benzoyl-4-[(4-methoxy-7-(1-methyl-pyrrol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₆N₅O₄: 472.20. found 470.26. HPLCretention time: 1.11 minutes (column A).

Example 29

Example 29, was prepared according to the general method described abovestarting from Precursor 5i and 1-methylpyrazol-3-yltributyltin, toprovide1-benzoyl-4-[(4-fluoro-7-(1-methyl-pyrazol-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₂FN₆O₃: 461.17. found 461.24. HPLCretention time: 1.36 minutes (column A).

Example 30

Example 30, was prepared according to the general method described abovestarting from Precursor 5i and pyridazin-4-yl tributyltin, Precursor14-8, to provide1-benzoyl-4-[(4-fluoro-7-(pyridazin-4-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine¹H NMR (500 MHz, CD₃OD) δ 9.72 (s, 1H), 9.39 (s, 1H), 8.42 (m, 2H), 8.22(s, 1H), 7.47 (s, 5H), 3.84-3.38 (m, 8H). MS m/z: (M+H)⁺ Calc'd forC₂₄H₂₀FN₆O₃: 459.16. found 459.25. HPLC retention time: 1.26 minutes(column A).

Example 32

Example 32, was prepared according to the general method described abovestarting from Precursor 5b and pyrazin-2-yl tributyltin, Precursor14a-1, to provide1-benzoyl-4-[(4-methoxy-7-(pyrazin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₆O₃: 471.18. found 471.17. HPLCretention time: 1.35 minutes (column A).

Example 33

Example 33, was prepared according to the general method described abovestarting from Precursor 5a and pyrazin-2-yl tributyltin, Precursor14a-1, to provide1-benzoyl-3-(R)-methyl-4-[(7-(pyrazin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₆O₃: 455.18. found 455.26. HPLCretention time: 1.46 minutes (column A).

Example 34

Example 34, was prepared according to the general method described abovestarting from Precursor 5g and pyrazin-2-yl tributyltin, Precursor14a-1, to provide1-benzoyl-4-[(7-(pyrazin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MSm/z: (M+H)⁺ Calc'd for C₂₄H₂₁N₆O₃: 441.17. found 441.22. HPLC retentiontime: 1.22 minutes (column A).

Example 35

Example 35, was prepared according to the general method described abovestarting from Precursor 5b and thiazol-2-yl tributyltin, Precursor14a-21, to provide1-(benzoyl)-4-[(4-methoxy-7-(thiazol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₂N₅O₃S: 476.14. found 476.20. HPLCretention time: 1.25 minutes (column B).

Example 36

Example 36, was prepared according to the general method described abovestarting from Precursor 5b and pyridin-2-yl tributyltin, Precursor14a-19, to provide1-benzoyl-4-[(4-methoxy-7-(pyridin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₄N₅O₄: 470.18. found 470.17. HPLCretention time: 1.04 minutes (column A).

Example 37

Example 37, was prepared according to the general method described abovestarting from Precursor 5j and thiazol-2-yl tributyltin, Precursor14a-21, to provide1-benzoyl-3-(R)-methyl-4-[(4-fluoro-7-(thiazol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₁FN₅O₃S 478.13. found 478.13. HPLCretention time: 1.34 minutes (column A).

Example 38

Example 38, was prepared according to the general method described abovestarting from Precursor 5i and pyrazol-3-yl tributyltin, to provide1-benzoyl-4-[(4-fluoro-7-(pyrazol-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazineMS m/z: (M+H)⁺ Calc'd for C₂₃H₂₀FN₆O₃: 447.16. found 447.15. HPLCretention time: 1.26 minutes (column A).

Example 39

Example 39, was prepared according to the general method described abovestarting from Precursor 5b and pyrazol-3-yl tributyltin, to provide1-benzoyl-4-[(4-methoxy-7-(pyrazol-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₃N₆O₄: 459.18. found 459.21. HPLCretention time: 1.11 minutes (column A).

Example 40

Example 40, was prepared according to the general method described abovestarting from Precursor 5b and pyrimidin-5-yl tributyltin, Precursor14-9, to provide1-benzoyl-4-[(4-methoxy-7-(pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazineMS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₆O₄: 471.18. found 471.20. HPLCretention time: 1.61 minutes (column A).

Example 41

Example 41, was prepared according to the general method described abovestarting from Precursor 5j and pyrimidin-5-yl tributyltin, Precursor14-9, to provide1-benzoyl-3-(R)-methyl-4-[(4-fluoro-7-(pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;¹H NMR (500 MHz, CD₃OD) δ 9.26 (m, 3H), 8.39 (m, 2H), 7.56 (m, 5H),4.72-3.12 (m, 7H), 1.40-0.91 (m, 3H). MS m/z: (M+H)⁺ Calc'd forC₂₅H₂₂FN₆O₃: 473.17. found 473.17. HPLC retention time: 1.34 minutes(column A).

Example 42

Example 42, was prepared according to the general method described abovestarting from Precursor 5i and pyrimidin-5-yl tributyltin, Precursor14-9, to provide1-benzoyl-4-[(4-fluoro-7-(pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₀FN₆O₃: 459.16. found 459.14. HPLCretention time: 1.28 minutes (column A).

Example 43

Example 43,(R)-1-(benzoyl)-3-methyl-4-[(7-(2,4-dimethoxy-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazineMS m/z: (M+H)⁺ Calc'd for C₂₇H₂₇N₆O₅: 515.20. found 515.28. HPLCretention time: 1.17 minutes (column B).

Example 44

Example 44, was prepared according to the general method described abovestarting from Precursor 5a and 2,3-dichloropyrazin-5-yltributyltin,Precursor 14-66, to provide1-benzoyl-3-(R)-methyl-4-[(7-(2,3-dichloro-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+Na)⁺ Calc'd for C₂₅H₂₀Cl₂NaN₆O₃: 545.09. found 545.29. HPLCretention time: 1.87 minutes (column B).

Example 45

Example 45, was prepared according to the general method described abovestarting from Precursor 5b and 2-ethoxythiazol-5-yl tributyltin,Precursor 14-71, to provide1-benzoyl-4-[(4-methoxy-7-(2-ethoxy-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₆N₅O₅S: 520.17. found 520.24. HPLCretention time: 1.32 minutes (column A).

Example 46

Example 46, was prepared according to the general method described abovestarting from Precursor 5b and the 2-amino-pyrazin-6-yl stannane,Precursor 14-68, to provide1-benzoyl-4-[(4-methoxy-7-(2-amino-pyrazin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₄N₇O₄: 486.19. found 486.31. HPLCretention time: 1.22 minutes (column B).

Example 47

Example 47, was prepared according to the general method described abovestarting from Precursor 5b and2-methylsulfonylamino-5-(tri-n-butylstannyl)pyrazine, Precursor 14-69,to provide1-benzoyl-4-[(7-(2-methylsulfonylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazineMS m/z: (M+H)⁺ Calc'd for C₂₆H₂₆N₇O₆S: 564.17. found 564.21. HPLCretention time: 1.24 minutes (column A).

Example 48

Example 48, was prepared according to the general method described abovestarting from Precursor 5b and 2,4-dimethoxy-1,3,5-triazin-6-yltributyltin, Precursor 14-70, to provide1-benzoyl-4-[(7-(2,4-dimethoxy-1,3,5-triazin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₆N₇O₆: 532.19. found 532.12. HPLCretention time: 1.28 minutes (column A).

Example 49

Example 49, was prepared according to the general method described abovestarting from Precursor 5b and pyrimidin-2-yl tributyltin, Precursor14-67, to provide1-benzoyl-4-[(4-methoxy-7-(pyrimidin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₆O₄: 471.18. found 471.29. HPLCretention time: 1.21 minutes (column A).

Example 50

Example 50, was prepared from1-(pyridin-2-yl)-4-[(4-methoxy-7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazineand thiazol-2-yl tributyltin, Precursor 14a-21, according to the generalmethod above to provide1-(pyridin-2-yl)-4-[(4-methoxy-7-(thiazol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazineMS m/z: (M+H)⁺ Calc'd for C₂₄H₂₅N₆O₄S: 477.13. found 477.22. HPLCretention time: 0.98 minutes (column A).

Example 51

Example 51, was prepared according to the general method described abovestarting from Precursor 5d and pyrimidin-5-yl tributyltin, Precursor14-9, to provide1-benzoyl-3-(R)-methyl-4-[(7-(pyrimidin-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₆O₃: 455.18. found 455.16. HPLCretention time: 0.98 minutes (column A).

Example 52

Example 52, was prepared according to the general method described abovestarting from Precursor 5d and pyrimidin-2-yl tributyltin, Precursor14a-1, to provide1-benzoyl-3-(R)-methyl-4-[(7-(pyrazin-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₆O₃: 455.18. found 455.16. HPLCretention time: 1.09 minutes (column A).

Example 53

Example 53, was prepared according to the general method described abovestarting from Precursor 5d and thiazol-2-yl tributyltin, Precursor14a-21, to provide1-benzoyl-3-(R)-methyl-4-[(7-(thiazol-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₂N₅O₃S: 460.14. found 460.26. HPLCretention time: 1.02 minutes (column A).

Example 54

Example 54, was prepared according to the general method described abovestarting from Precursor 5d and 2-ethoxythiazol-5-yl tributyltin,Precursor 14-71, to provide1-benzoyl-3-(R)-methyl-4-[(7-(2-ethoxy-thiazol-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₆N₅O₄S: 504.17. found 4504.18. HPLCretention time: 1.26 minutes (column A).

Example 55

The compound of Example 15,1-benzoyl-4-[(4-methoxy-7-(2-(1,1-dimethylethylaminocarbonyl)-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine(20 mg) was dissolved in 1 drop of concentrated sulfuric acid. After 30minutes, the mixture was diluted with 2 mL of methanol. The resultingsolution was injected into a Shimadzu automated preparative HPLC Systemand the HPLC purification afforded the compound of Example 55,1-benzoyl-4-[(4-methoxy-7-(2-aminocarbonyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine(1 mg); MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₄N₇O₅: 514.78. found 514.22. HPLCretention time: 1.44 minutes (column B).

Example 56

An excess of NH₄Cl (27 mg) was added into a solution of1-(benzoyl)-3-(R)-methyl-4-[(6-cyano-7-azaindol-3-yl)-oxoacetyl]piperazine(20 mg) and NaN₃ (16 mg) in DMF. The reaction was heated to reflux for12 h. After cooling down, the mixture was concentrated under reducedpressure and the residue was purified using Shimadzu automatedpreparative HPLC System to give1-benzoyl-3-(R)-methyl-4-[(6-(tetrazol-1-yl)-7-azaindol-3-yl)-oxoacetyl]piperazine(6.3 mg). MS m/z: (M+H)⁺ Calc'd for C₂₂H₂₁N₈O₃: 445.17. Found 3445.16.HPLC retention time: 1.42 minutes (column B); Column B: PHX-LUNA C184.6×30 mm.

Example 57

Preparation of1-benzoyl-3-(R)-methyl-4-[(7-(methoxymethylamino)carbonyl)-4-azaindol-3-yl)-oxoacetyl]piperazine:A mixture of Precursor 13 (267 mg), N,O-dimethylhydroxylamine hydrogenchloride (248 mg), carbon tetrabromide (844 mg), pyridine (202 mg) andtriphenylphosphine (668 mg) in dichloromethane (10 mL) was stirred atroom temperature for 10 hours. After solvent was removed under vacuum,the residue was purified by using silica gel chromatography to afford1-(benzoyl)-3-(R)-methyl-4-[(7-(methoxymethylamino)carbonyl)-4-azaindol-3-yl)-oxoacetyl]piperazine(56 mg); MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₆N₅O₅: 464.19. found 464.25.HPLC retention time: 1.02 minutes (column A).

Example 58

Example 58 was prepared according to the same procedure used inpreparing Example 57 with the exception of using Precursor 11 as astarting material instead of Precursor 13. The procedure provided1-benzoyl-3-(R)-methyl-4-[(5-chloro-(7-(methoxymethylamino)carbonyl)-4-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₅ClN₅O₅: 498.15. found 498.12. HPLCretention time: 1.39 minutes (column A).

General Procedure A to Prepare CO—NR1R2 from COOH

Example 59

Preparation of1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(methylamino)carbonyl)-4-azaindol-3-yl)-oxoacetyl]piperazine:A mixture of Precursor 11 (25 mg), methylamine (2M in THF, 0.08 mL), EDC(26 mg), HOBT (11.2 mg) and diisopropylethylamine (43 mg) intetrahydrofuran (5 mL) was stirred at room temperature for 10 hours.After the solvent was removed under vacuum, the residue was purified byusing silica gel chromatography to afford1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(methylamino)carbonyl)-4-azaindol-3-yl)-oxoacetyl]piperazine(13.6 mg); MS m/z: (M+H)⁺ Calc'd for C₂₃H₂₃ClN₅O₄: 468.14. found 468.03.HPLC retention time: 1.33 minutes (column A).

This general produre A is applied to prepare examples 94 and 135:

Example 94

Example 94,1-benzoyl-4-[(4-methoxy-7-(2-methylaminocarbonyl-furan-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ8.37 (s, 1H), 8.06 (s, 1H), 7.48-7.26 (m, 7H),4.08 (s, 3H), 3.83-3.44 (m, 8H), 2.96 (s, 3H). MS m/z: (M+H)⁺ Calc'd forC₂₉H₂₆N₅O₆: 516.19. found 516.14. HPLC retention time: 1.35 minutes(column A).

Example 135

Example 135, (R)-1-benzoyl-3-methyl-4-[(7-(4-trifluoromethylbenzylamino)carbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H)⁺ Calc'dfor C₃₀H₂₇F₃N₅O₄: 578.20. found 578.39. HPLC retention time: 1.47minutes (column G).

General Procedure B to Prepare CO—NR1R2 from COOH

Preparation of Example 136,(R)-1-benzoyl-3-methyl-4-[(7-(4-methylthiazol-2-yl)aminocarbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine:

To a solution of(R)-1-benzoyl-3-methyl-4-[(7-hydroxylcarbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine(146 mg) in DMF (5 ml) at room temperature was added pentafluorophenyl(70.3 mg) followed by EDC (73.23 mg). The reaction mixture was stirredat room temperature for 8 hours. The crude product was diluted withmethylene chloride and was washed with water, 0.1N HCl and brine. Theorganic phase was dried over MgSO4, filtered and concentrated. Thepentafluorophenyl ester was used in the following reaction withoutfurther purification.

To a stirred solution of 4-methyl-2-amino-thiazole (39.6 mg) and Hunig'sbase (49.4 mg) in DMF (5 ml) at room temperature was added a solution ofpentafluorophenyl ester (⅓ of the product obtained in the previous stepdescribed above) in DMF (2 ml). The reaction mixture was stirred at roomtemperature for 16 hours. The crude product was diluted with methylenechloride and was washed with Na2CO3 (sat.) and brine. The organic phasewas dried over MgSO4, filtered and concentrated. The residue waspurified using Shimadzu automated preparative HPLC System to give(R)-1-benzoyl-3-methyl-4-[(7-(4-methylthiazol-2-yl)aminocarbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine(3.6 mg). MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₅N₆O₄S: 517.17. found 517.41.HPLC retention time: 1.25 minutes (column A).

This general produre B is applied to prepare example 137:

Example 137

Example 137,(R)-1-benzoyl-3-methyl-4-[(7-(thiazol-2-yl)aminocarbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₆O₄S: 503.15. found 503.29. HPLCretention time: 1.33 minutes (column A).

Example 60

Preparation of1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(imidazol-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine:A mixture of Precursor 10 (34 mg), glyoxal (40% in water, 0.2 mL) andammonia acetate (139 mg) in methanol was heated up to reflux for 10hours. After cooling down, the mixture was concentrated under reducedpressure and the residue was purified using Shimadzu automatedpreparative HPLC System to provide1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(imidazol-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine(1.8 mg); MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₂ClN₆O₃: 477.14. found 477.13.HPLC retention time: 1.17 minutes (column A).

Example 61

Example 61 was prepared according to the same procedure used forpreparing Example 60 with the exception of using methylglyoxal as astarting material instead of glyoxal to provide1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(4-methyl-imidazol-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazineMS m/z: (M+H)⁺ Calc'd for C₂₅H₂₄ClN₆O₃: 491.16. found 491.13. HPLCretention time: 1.26 minutes (column A).

Example 62

Example 62 was prepared according to the same procedure used forpreparing Example 60 with the exception of using dimethylglyoxal as astarting material instead of glyoxal to provide1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(4,5-dimethyl-imidazol-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₆ClN₆O₃: 505.18. found 505.10. HPLCretention time: 1.24 minutes (column A).

Example 63

Preparation of1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(oxazol-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine:A mixture of Precursor 10 (27.6 mg), tosylmethyl isocyanide (12.3 mg)and K₂CO₃ (8.7 mg) in MeOH was heated up to reflux for 10 hours. Aftercooling down, the mixture was concentrated under reduced pressure andthe residue was purified using Shimadzu automated preparative HPLCSystem to provide1-(benzoyl)-3-(R)-methyl-4-[(5-chloro-7-(oxazol-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine(17.7 mg); MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₁ClN₅O₄: 478.13. found 478.03.HPLC retention time: 1.48 minutes (column A).

Example 64

Step 1: Preparation of 1-64,1-benzoyl-3-(R)-methyl-4-[(7-(2-propynyl)carbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine:Propynyllithium (21 mg) was added to a solution of Example 52 (41 mg) intetrahydrofuran (5 ml) at −78° C. The reaction was quenched withmethanol at −25° C. in 2 hours. After solvents were removed undervacuum, the residue was carried to the further reactions without anypurification. 1-64,1-benzoyl-3-(R)-methyl-4-[(7-(2-propynyl)carbonyl-4-azaindol-3-yl)-oxoacetyl]piperazineMS m/z: (M+H)⁺ Calc'd for C₂₅H₂₂ClN₄O₄: 477.13. found 477.17. HPLCretention time: 1.46 minutes (column A).

Step 2: Preparation of Example 64

Preparation of Example 64,1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(3-methyl-pyrazol-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine:A mixture of 1-64 (crude product from Step 1) and hydrazine (0.22 mL) inEtOAc (2 mL) and water (2 mL) was stirred at room temperature for 24hours. Then solvents were removed under vacuum, and the residue waspurified using Shimadzu automated preparative HPLC System to give1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(3-methyl-pyrazol-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine(9 mg); MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₄ClN₆O₃: 491.16. found 491.19.HPLC retention time: 1.42 minutes (column A).

Examples 65-67

The procedure for the preparation of Examples 65-67 is the same as thatdescribed previously for the preparation of Precursor 5a and is asfollows: Potassium 7-(4-methoxyphenyl)-4-azaindole-3-glyoxylate,Precursor 4c (147 mg, 0.44 mmol), an appropriate 1-benzoylpiperazinederivative (0.44 mmol),3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) (101 mg,0.44 mol) and Hunig's Base (0.5 mL) were combined in 5 mL of DMF. Themixture was stirred at rt for 8 h. DMF was removed via evaporation atreduced pressure and the residue was purified using a Shimadzu automatedpreparative HPLC System to give the corresponding1-benzoyl-4-[(7-(4-methoxyphenyl)-4-azaindol-3-yl)-oxoacetyl]-piperazinederivative.

Example 65

Example 19,1-(benzoyl)-4-[(7-(4-methoxy)-4-azaindol-3-yl)-oxoacetyl]piperazine wasprepared from potassium 7-(4-methoxyphenyl)-4-azaindole-3-glyoxylate and1-(benzoyl)piperazine according to the above general procedure. MS m/z:(M+H)⁺ Calc'd for C₂₇H₂₅N₄O₄: 469.19. found 469.16. HPLC retention time:1.26 minutes (column A).

Example 66

Example 66,1-benzoyl-3-(S)-methyl-4-[(7-(4-methoxy)-4-azaindol-3-yl)-oxoacetyl]piperazinewas prepared from potassium 7-(4-methoxyphenyl)-4-azaindole-3-glyoxylateand the corresponding 1-(benzoyl)-3-methylpiperazine according to theabove general procedure. MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₇N₄O₄: 483.20.found 483.17. HPLC retention time: 1.30 minutes (column A).

Example 67

Example 67,1-benzoyl-3-(R)-methyl-4-[(7-(4-methoxyphenyl)-4-azaindol-3-yl)oxoacetyl]piperazinewas prepared from potassium 7-(4-methoxyphenyl)-4-azaindole-3-glyoxylateand the corresponding 1-benzoyl-3-methylpiperazine according to theabove general procedure. MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₇N₄O₄: 483.20.found 483.16. HPLC retention time: 1.28 minutes (column A).

Examples 68-79 and 81

Examples 68-79 and 81 were prepared according to the same general methodas previously described for Examples 16-54.

Example 68

Example 68, was prepared from Precursor 5b and the2,4-dimethoxypyrimidin-6-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2,6-dimethoxy-pyrimidin-4-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CDCl₃) δ 8.20 (s, 1H), 8.13 (s, 1H), 7.52 (s, 1H), 7.42(m, 5H), 4.11 (s, 3H), 4.06 (s, 3H), 4.00-3.40 (m, 8H). MS m/z: (M+H)⁺Calc'd for C₂₇H₂₇N₆O₆: 531.20. found 531.24. HPLC retention time: 1.54minutes (column A).

Example 69

Example 69, was prepared from Precursor 5b and the 6-methoxypyridin-3-ylstannane to provide1-benzoyl-4-[(4-methoxy-7-(6-methoxy-pyridin-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ 8.69 (s, 1H), 8.63 (s, 1H), 8.11 (m, 2H), 7.49(m, 5H), 7.10 (d, 1H, J=8.65 Hz), 4.16 (s, 3H), 4.06 (s, 3H), 4.00-3.40(m, 8H). MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₆N₅O₅: 500.09. found 500.20.HPLC retention time: 1.11 minutes (column A).

Example 70

Example 70, was prepared from Precursor 5b and the2-diethylamino-thiazol-4-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2-diethylamino-thiazol-4-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ 8.47 (s, 1H), 7.97 (m, 2H), 7.49 (m, 5H), 4.08(s, 3H), 3.64 (m, 12H), 1.35 (m, 6H). MS m/z: (M+H)⁺ Calc'd forC₂₈H₃₁N₆O₄S: 547.21. found 547.22. HPLC retention time: 1.35 minutes(column A).

Example 71

Example 71, was prepared from Precursor 5b and the thiazol-5-yl stannaneto provide1-benzoyl-4-[(4-methoxy-7-(thioazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.64 (s, 1H), 8.34 (s, 1H),8.11 (s, 1H), 7.46 (m, 5H), 4.00 (s, 3H), 3.55 (m, 8H). MS m/z: (M+H)⁺Calc'd for C₂₄H₂₂N₅O₄S: 476.14. found 476.17. HPLC retention time: 1.13minutes (column A).

Example 72

Example 72, was prepared from Precursor 5b and the2-dimethylamino-pyrazin-5-yl stannane to provide1-(benzoyl)-4-[(4-methoxy-7-(2-dimethylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₈N₇O₄: 514.22. found 514.29. HPLCretention time: 1.27 minutes (column A).

Example 73

Example 73, was prepared from Precursor 5b and the furan-2-yl stannaneto provide1-(benzoyl)-4-[(4-methoxy-7-(furan-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₄O₅: 459.17. found 459.25. HPLCretention time: 1.15 minutes (column A).

Example 74

Example 74, was prepared from Precursor 5b and the oxazol-2-yl stannaneto provide1-benzoyl-4-[(4-methoxy-7-(oxazol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.64 (s, 1H), 8.34 (s, 1H),8.11 (s, 1H), 7.46 (m, 5H), 4.00 (s, 3H), 3.55 (m, 8H). MS m/z: (M+H)⁺Calc'd for C₂₄H₂₂N₅O₅: 460.16. found 460.23. HPLC retention time: 1.22minutes (column A).

Example 75

Example 75, was prepared from Precursor 5b and the 6-aminopyridin-2-ylstannane to provide1-benzoyl-4-[(4-methoxy-7-(2-aminopyridin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₅N₆O₄: 485.19. found 485.24. HPLCretention time: 1.15 minutes (column A).

Example 76

Example 76, was prepared from Precursor 5b and the 6-methylpyridin-2-ylstannane to provide1-benzoyl-4-[(4-methoxy-7-(2-methyl-pyridin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₆N₅O₄: 484.20. found 484.22. HPLCretention time: 1.24 minutes (column A).

Example 77

Example 77, was prepared from Precursor 5b and the 6-methoxypyridin-2-ylstannane to provide1-benzoyl-4-[(4-methoxy-7-(2-methoxy-pyridin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₆N₅O₅: 500.19. found 500.23. HPLCretention time: 1.26 minutes (column A).

Example 78

Example 78, was prepared from Precursor 5b and the2-acetylamino-thiazol-5-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2-acetylamino-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₅N₆O₅S: 533.16. found 533.18. HPLCretention time: 1.21 minutes (column A).

Example 79

Example 79, was prepared from Precursor 5b and the2-ethylamino-pyrazin-5-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2-ethylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₈N₇O₄: 514.22. found 514.18. HPLCretention time: 1.31 minutes (column A).

Example 88

Example 88, was prepared from Precursor 5b and the 2-ethyl-thiazol-5-ylstannane to provide1-benzoyl-4-[(4-methoxy-7-(2-ethyl-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₆N₅O₄S: 504.17. found 514.32. HPLCretention time: 1.50 minutes (column A).

Example 89

Example 89, was prepared from Precursor 5k and the2-isobutyl-thiazol-5-yl stannane to provide1-benzoyl-4-[(7-(2-isobutyl-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₈N₅O₃S: 502.19. found 502.26. HPLCretention time: 1.56 minutes (column E).

Example 90

Example 90, was prepared from Precursor 5b and the2-isobutyl-thiazol-5-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2-isobutyl-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₈H₃₀N₅O₄S: 532.20. found 532.27. HPLCretention time: 1.57 minutes (column E).

Example 91

Example 91, was prepared from Precursor 5b and the2-(2-butyl)-thiazol-5-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2-(2-butyl)-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₈H₃₀N₅O₄S: 532.20. found 532.27. HPLCretention time: 1.57 minutes (column E).

Example 92

Example 92, was prepared from Precursor 5b and the2-(thiazol-2-yl)-thiazol-5-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2-(thiazol-2-yl)-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₃N₆O₄S₂: 559.12. found 559.18. HPLCretention time: 1.55 minutes (column E).

Example 93

Example 93, was prepared from Precursor 5b and the2-methylthio-thiazol-5-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2-methylthio-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₄N₅O₄S₂: 522.13. found 522.17. HPLCretention time: 1.45 minutes (column E).

Example 95

Example 95, was prepared from Precursor 5i and the pyrazin-2-yl stannaneto provide1-benzoyl-4-[(4-fluoro-7-(pyrazin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CDCl₃) 69.89 (s, 1H), 8.70-8.34 (m, 4H), 7.46 (m, 5H),3.80-3.50 (m, 8H). MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₀FN₆O₃: 459.16. found459.33. HPLC retention time: 1.46 minutes (column G).

Example 100

Example 100, was prepared from Precursor 5b and the2-methylamino-3-methoxy-pyrazin-5-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2-methylamino-3-methoxy-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ8.65 (s, 1H), 8.43 (s, 1H), 7.95 (s, 1H), 7.45(m, 5H), 4.21 (s, 3H), 4.12 (s, 3H), 3.89-3.32 (m, 8H), 3.06 (s, 3H). MSm/z: (M+H)⁺ Calc'd for C₂₇H₂₈N₇O₅: 530.22. found 530.19. HPLC retentiontime: 1.31 minutes (column A).

Example 101

Example 101, was prepared from Precursor 5b and the2-amino-3-methoxy-pyrazin-5-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2-amino-3-methoxy-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ8.67 (s, 1H), 8.34 (s, 1H), 7.96 (s, 1H), 7.48(m, 5H), 4.22 (s, 3H), 4.12 (s, 3H), 3.92-3.32 (m, 8H). MS m/z: (M+H)⁺Calc'd for C₂₆H₂₆N₇O₅: 516.20. found 516.23. HPLC retention time: 1.27minutes (column A).

Example 102

Example 102, was prepared from Precursor 51 and the pyrazin-2-ylstannane to provide1-picolinoyl-4-[(4-methoxy-7-(pyrazin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ9.59 (s, 1H), 8.79-7.51 (m, 8H), 4.13 (s, 3H),3.95-3.34 (m, 8H). MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₂N₇O₄: 472.17. found472.25. HPLC retention time: 1.15 minutes (column A).

Example 103

Example 103, was prepared from Precursor 51 and the2-dimethylamino-pyrazin-5-yl stannane to provide1-picolinoyl-4-[(4-methoxy-7-(2-dimethylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₇N₈O₄: 515.22. found 515.16. HPLCretention time: 1.29 minutes (column A).

Example 104

Example 104, was prepared from Precursor 5b and the6-aza-benzofuran-2-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(6-aza-benzofuran-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CDCl₃) δ 8.48 (d, 1H, J=8.5 Hz), 8.36 (s, 1H), 8.30 (s,1H), 8.02 (s, 1H), 7.64 (d, 1H, J=8.55 Hz), 7.41 (m, 4H), 6.92 (s, 1H),4.12 (s, 3H), 3.87-3.38 (m, 8H). MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₄N₅O₅:510.18. found 510.33. HPLC retention time: 1.33 minutes (column A).

Example 105

Example 105, was prepared from Precursor 5m and the2-dimethylamino-pyrazin-5-yl stannane to provide(R)-1-picolinoyl-3-methyl-4-[(7-(2-dimethylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₇N₈O₃: 499.22. found 499.27. HPLCretention time: 1.17 minutes (column A).

Example 106

Example 106, was prepared from Precursor 5n and the2-dimethylamino-pyrazin-5-yl stannane to provide(S)-1-picolinoyl-3-methyl-4-[(7-(2-dimethylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ9.08-7.49 (m, 9H), 5.00-3.15 (m, 13H),1.44-1.27 (m, 3H). MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₇N₈O₃: 499.22. found499.27. HPLC retention time: 1.19 minutes (column A).

Example 109

Example 109, was prepared from Precursor 5m and the thiazol-5-ylstannane to provide(R)-1-picolinoyl-3-methyl-4-[(7-(thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ9.42-7.49 (m, 9H), 4.98-3.14 (m, 7H), 1.43-1.26(m, 3H). MS m/z: (M+H)⁺ Calc'd for C₂₃H₂₁N₆O₃S: 461.14. found 461.28.HPLC retention time: 1.11 minutes (column A).

Example 110

Example 110, was prepared from Precursor 5n and the thiazol-5-ylstannane to provide(S)-1-picolinoyl-3-methyl-4-[(7-(thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ9.44-7.48 (m, 9H), 4.98-3.15 (m, 7H), 1.43-1.26(m, 3H). MS m/z: (M+H)⁺ Calc'd for C₂₃H₂₁N₆O₃S: 461.14. found 461.27.HPLC retention time: 1.13 minutes (column A).

Example 111

Example 111, was prepared from Precursor 5f and the 2-amino-pyrazin-6-ylstannane to provide(R)-1-benzoyl-3-methyl-4-[(7-(2-amino-pyrazin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ8.68-7.45 (m, 10H), 4.89-3.13 (m, 7H),1.39-0.99 (m, 3H). MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₄N₇O₃: 470.19. found470.31. HPLC retention time: 1.30 minutes (column A).

Example 112

Example 112, was prepared from Precursor 5f and the 2-amino-pyridin-6-ylstannane to provide(R)-1-benzoyl-3-methyl-4-[(7-(2-amino-pyridin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ8.65-6.89 (m, 11H), 4.90-3.12 (m, 7H),1.39-0.99 (m, 3H). MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₅N₆O₃: 469.20. found469.32. HPLC retention time: 1.26 minutes (column A).

Example 113

Example 113, was prepared from Precursor 5f and the 2-amino-pyridin-5-ylstannane to provide(R)-1-benzoyl-3-methyl-4-[(7-(2-amino-pyridin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ8.75-7.19 (m, 11H), 4.91-3.12 (m, 7H),1.38-1.25 (m, 3H). MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₅N₆O₃: 469.20. found469.34. HPLC retention time: 1.05 minutes (column A).

Example 114

Example 114, was prepared from Precursor 5f and the 5-amino-pyridin-2-ylstannane to provide(R)-1-benzoyl-3-methyl-4-[(7-(5-amino-pyridin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ8.67-7.20 (m, 11H), 4.88-3.13 (m, 7H),1.39-1.25 (m, 3H). MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₅N₆O₃: 469.20. found469.33. HPLC retention time: 1.22 minutes (column A).

Example 115

Example 115, was prepared from Precursor 5b and the2-methylamino-pyrazin-5-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2-methylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ8.90 (s, 1H), 8.61 (s, 1H), 8.18 (s, 1H), 7.92(s, 1H), 7.46 (m, 5H), 4.12 (s, 3H), 3.85-3.40 (m, 8H), 3.02 (s, 3H). MSm/z: (M+H)⁺ Calc'd for C₂₆H₂₆N₇O₄: 500.20. found 500.23. HPLC retentiontime: 1.24 minutes (column A).

Example 116

Example 116, was prepared from Precursor 5b and the2-(2-pyrrolidinon-1-yl)-thiazol-5-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-((2-pyrrolidinon-1-yl)-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₂N₆O₅S₂: 559.18. found 559.11. HPLCretention time: 1.39 minutes (column E).

Example 117

Example 117, was prepared from Precursor 5b and the2-methoxy-pyrimidin-5-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2-methoxy-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₅N₆O₅: 501.19. found 501.12. HPLCretention time: 1.21 minutes (column E).

Example 118

Example 118, was prepared from Precursor 5b and the2-(pyrrol-1-yl)-pyrimidin-5-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2-(pyrrol-1-yl)-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₉H₂₆N₇O₄: 536.20. found 536.33. HPLCretention time: 1.44 minutes (column C).

Example 119

Example 119, was prepared from Precursor 5b and the pyrimidin-4-ylstannane to provide1-benzoyl-4-[(4-methoxy-7-(pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ9.29 (s, 1H), 8.88 (d, 1H, J=5.4 Hz), 8.48 (d,1H, J=5.25 Hz), 8.26 (s, 1H), 8.18 (s, 1H), 7.43 (m, 5H), 4.13 (s, 3H),3.85-3.47 (m, 8H). MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₆O₄: 471.18. found471.32. HPLC retention time: 1.35 minutes (column G).

Example 120

Example 119, was prepared from Precursor 5b and the pyridazin-3-ylstannane to provide1-benzoyl-4-[(4-methoxy-7-(pyridazin-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ9.16 (s, 1H), 8.77 (d, 1H, J=8.5 Hz), 8.26 (d,1H, J=3.05 Hz), 8.18 (s, 1H), 7.68 (m, 1H), 7.43 (m, 5H), 4.13 (s, 3H),3.85-3.47 (m, 8H). MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₆O₄: 471.18. found471.16. HPLC retention time: 1.35 minutes (column G).

Example 125

Example 125, was prepared from Precursor 5i and the pyrimidin-4-ylstannane to provide1-benzoyl-4-[(4-fluoro-7-(pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ9.36 (s, 1H), 8.96 (d, 1H, J=5.35 Hz), 8.58 (d,1H, J=5.10 Hz), 8.43 (s, 1H), 8.38 (s, 1H), 7.43 (m, 5H), 3.85-3.47 (m,8H). MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₀FN₆O₂: 459.16. found 459.15. HPLCretention time: 1.48 minutes (column A).

Example 126

Example 126, was prepared from Precursor 5i and the oxazol-2-yl stannaneto provide(R)-1-benzoyl-3-Methyl-4-[7-(oxazol-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₂N₅O₄: 444.17. found 444.25. HPLCretention time: 1.13 minutes (column A).

Example 131

Example 131, was prepared from Precursor 5p and the thiazol-2-ylstannane to provide1-benzoyl-4-[(7-(thiazol-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine. MSm/z:

(M+H)⁺ Calc'd for C₂₃H₂₀N₅O₃S: 446.13. found 446.04. HPLC retentiontime: 1.12 minutes (column A).

Example 80

Preparation of Example 80,1-benzoyl-4-[(4-methoxy-7-(2-amino-thioazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine:A mixture of Example 78 (9 mg), TFA (3 mL) and water (1 mL) was stirredat 80° C. for 10 hours. After solvent was removed under vacuum, theresidue was purified by using silica gel chromatography to afford1-benzoyl-4-[(4-methoxy-7-(2-amino-thioazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine(3 mg); MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₃N₆O₅S: 491.15. found 491.21.HPLC retention time: 1.20 minutes (column A).

Example 81

Example 81, was prepared from Precursor 5b and the furan-3-yl stannaneto provide1-benzoyl-4-[(4-methoxy-7-(furan-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₄O₅: 459.17. found 459.24. HPLCretention time: 1.13 minutes (column A).

Example 150

Example 150, was prepared from Precursor 5f and the 5-amino-pyrazin-2-ylstannane to provide(R)-1-benzoyl-3-methyl-4-[(7-(5-amino-pyrazin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₄N₇O₃: 470.19. found 470.19. HPLCretention time: 1.14 minutes (column G).

Example 153

Example 153, was prepared from Precursor 5f and the2-amino-pyrimidin-5-yl stannane to provide(R)-1-benzoyl-3-methyl-4-[(7-(2-amino-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₄N₇O₃: 470.19. found 470.22. HPLCretention time: 1.07 minutes (column G).

Example 170

Example 170, was prepared from Precursor 5f and the 4-borono-benzoicacid to provide(R)-1-benzoyl-3-methyl-4-[(7-(hydoxylcarbonyl-benzen-4-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₅N₄O₅: 497.18. found 497.10. HPLCretention time: 1.25 minutes (column H).

Example 171

Example 171, was prepared from Precursor 5b and the2-methyl-pyrimidin-5-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2-methyl-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₅N₆O₄: 485.19. found 485.20. HPLCretention time: 1.14 minutes (column C).

Example 172

Example 172, was prepared from Precursor 51 and the 5-indole boronicacid to provide1-picolinoyl-4-[(4-methoxy-7-(indol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₅N₆O₄: 509.19. found 509.33. HPLCretention time: 1.14 minutes (column J).

Example 173

Example 173, was prepared from Precursor 51 and the thiazol-4-ylstannane to provide1-picolinoyl-4-[(4-methoxy-7-(thiazol-4-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₃H₂₁N₆O₄S: 477.13. found 477.06. HPLCretention time: 0.92 minutes (column G).

Example 174

Example 174, was prepared from Precursor 5b and the thiazol-4-ylstannane to provide1-benzoyl-4-[(4-methoxy-7-(thiazol-4-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₂N₅O₄S: 476.14. found 476.13. HPLCretention time: 1.12 minutes (column G).

Example 175

Example 175, was prepared from Precursor 5b and the2-(N-diethylaminoethyl-N-methyl)aminopyrazin-5-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2-(N-diethylaminoethyl-N-methyl)aminopyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₃₂H₃₉N₈O₄: 599.31. found 599.29. HPLCretention time: 1.11 minutes (column G).

Example 176

Example 176, was prepared from Precursor 5b and the2-(N-dimethylaminoethyl-N-methyl)aminopyrazin-5-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2-(N-dimethylaminoethyl-N-methyl)aminopyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₃₀H₃₅N₈O₄: 571.28. found 571.23. HPLCretention time: 1.06 minutes (column G).

Example 177

Example 177, was prepared from Precursor 5b and the2-(N-piperazinyl)-pyrazin-5-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2-(N-piperazinyl)-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₉H₃₁N₈O₄: 555.25. found 555.19. HPLCretention time: 1.05 minutes (column G).

Example 178

Example 178, was prepared from Precursor 5b and the2-(4-morpholinyl)-pyrazin-5-yl stannane to provide1-benzoyl-4-[(4-methoxy-7-(2-(4-morpholinyl)-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₉H₃₀N₇O₅: 556.23. found 556.18. HPLCretention time: 1.27 minutes (column G).

Example 179

Example 179, was prepared from Precursor 51 and the2-ethylaminopyrazin-5-yl stannane to provide1-picolinoyl-4-[(4-methoxy-7-(2-ethylaminopyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₇N₈O₄: 515.22. found 515.14. HPLCretention time: 1.13 minutes (column G).

Example 180

Example 180, was prepared from Precursor 51 and the 2-methylpyrazin-5-ylstannane to provide1-picolinoyl-4-[(4-methoxy-7-(2-methylpyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₄N₇O₄: 486.19. found 486.16. HPLCretention time: 1.08 minutes (column G).

Example 181

Example 181, was prepared from Precursor 51 and the2-cyclopropanyl-pyrazin-5-yl stannane to provide1-picolinoyl-4-[(4-methoxy-7-(2-cyclopropanyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₆N₇O₄: 512.20. found 512.12. HPLCretention time: 1.35 minutes (column G).

Example 182

Example 182, was prepared from Precursor 51 and the2-methoxy-pyrazin-5-yl stannane to provide1-picolinoyl-4-[(4-methoxy-7-(2-methoxy-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₄N₇O₅: 502.18. found 502.08. HPLCretention time: 1.15 minutes (column G).

Example 183

Example 183, was prepared from Precursor 51 and the 2-benzofuran boronicacid to provide1-picolinoyl-4-[(4-methoxy-7-(benzofuran-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₄N₅O₅: 510.18. found 510.08. HPLCretention time: 1.33 minutes (column G).

Example 184

Example 184, was prepared from Precursor 51 and the2-diethylaminocarbonyl-pyrazin-5-yl stannane to provide1-picolinoyl-4-[(4-methoxy-7-(2-diethylaminocarbonyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₉H₃₁N₈O₅: 571.24. found 571.19. HPLCretention time: 1.55 minutes (column J)

Example 185

Example 185, was prepared from Precursor 51 and the2-(N-pyrrolinyl)-pyrazin-5-yl stannane to provide1-picolinoyl-4-[(4-methoxy-7-(2-(N-pyrrolinyl)-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₉N₈O₄: 541.23. found 541.18. HPLCretention time: 1.30 minutes (column J)

Example 186

Example 186, was prepared from Precursor 51 and the quinoxalin-2-ylstannane to provide1-picolinoyl-4-[(4-methoxy-7-(quinoxakin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₄N₇O₄: 522.19. found 522.14. HPLCretention time: 1.68 minutes (column J)

Example 194

Example 194, was prepared from Precursor 5v and the pyrazin-2-ylstannane to provide2-methyl-1-picolinoyl-4-[(4-methoxy-7-(pyrazin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₄N₇O₄: 486.19. found 486.14. HPLCretention time: 1.50 minutes (column G).

Example 147

Precursor 5i (16.5 mg, 0.05 mmol) in DMF (1 mL) was treated withN-benzoylpiperazine hydrochloride, DEBPT (15 mg, 0.05 mmol) and Hunig'sbase (34 μL, 0.2 mmol) at rt for 18 h. The solvent was removed in vacuumand the residue was purified by reverse phase preparative HPLC. Thefractions showing the right LC/MS (ES⁺) m/z (M+H)⁺ =501 were collected,concentrated and purified again using a preparative TLC (5% MeOH/CH₂Cl₂)to afford the title compound as a white solid. ¹H-NMR (500 MHz, CDCl₃) δ11.2 (s, 1H), 10.0 (s, 1H), 9.21 (s, 1H), 8.51 (s, 1H), 8.41 (s, 1H),8.40 (m, 1H), 8.32 (s, 1H), 7.62 (m, 1H), 7.45 (m, 5H), 3.90-3.50 (bm,8H).

Example 156

Example 156, was prepared from Precursor 5b and the4,4-dimethyloxazolin-2-yl stannane to provide1-benzoyl-4-[(7-(4,4-dimethyloxazolin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₈N₅O₅: 490.21. found 490.22. HPLCretention time: 1.20 minutes (column C).

Example 169

Example 169, was prepared from Precursor 5b and the2-(4-pyridinecarboxamido)-thiazol-5-yl stannane to provide1-benzoyl-4-[(7-(2-(4-pyridinecarboxamido)-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₃₀H₂₆N₇O₅S: 596.17. found 596.14. HPLCretention time: 1.32 minutes (column C).

Examples 82-86, 98, 107, 108, 129, 130, 132, 133, 134

Examples 82-86, 98, 107, 108, 127, 128, 129, 130, 132, 133 and 134 wereprepared according to the general procedure as previously described forExamples 2-14.

Example 82

Example 82, was prepared from Precursor 5b and thien-2-yl boronic acidto provide1-benzoyl-4-[(4-methoxy-7-(thiophen-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₄O₄S: 475.14. found 475.31. HPLCretention time: 1.14 minutes (column A).

Example 83

Example 83, was prepared from Precursor 5b and thien-2-yl boronic acidto provide1-benzoyl-4-[(4-methoxy-7-(thiophen-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₄O₄S: 475.14. found 475.33. HPLCretention time: 1.16 minutes (column A).

Example 84

Example 84, was prepared from Precursor 5b and 5-carbonylthien-2-ylboronic acid to provide1-benzoyl-4-[(4-methoxy-7-(5-carbonyl-thiophen-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₃N₄O₅S: 503.14. found 503.23. HPLCretention time: 1.31 minutes (column A).

Example 85

Example 76, was prepared from Precursor 5b and 5-carbonylfuran-2-ylboronic acid to provide1-(benzoyl)-4-[(4-methoxy-7-(5-carbonyl-furan-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₃N₄O₆: 487.16. found 487.28. HPLCretention time: 1.44 minutes (column A).

Example 86

Example 86, was prepared from Precursor 5d and 4-methylthien-2-ylboronic acid to provide1-benzoyl-3-(R)-methyl-4-[(7-(4-methyl-thiophen-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₅N₄O₃S: 473.16. found 473.26. HPLCretention time: 1.28 minutes (column A).

Example 98

Example 98, was prepared from Precursor 5d and 2-benzofuranyl boronicacid to provide1-benzoyl-3-(R)-methyl-4-[(7-(benzofuran-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CDCl₃) δ 8.24 (s, 1H), 8.09 (s, 1H), 7.70-7.26 (m,10H), 4.03 (s, 3H), 3.97-3.49 (m, 8H). MS m/z: (M+H)⁺ Calc'd forC₂₉H₂₅N₄O₅: 509.18. found 509.18. HPLC retention time: 1.50 minutes(column A).

Example 107

Example 107, was prepared from Precursor 5m and 2-benzofuranyl boronicacid to provide(R)-1-picolinoyl-3-methyl-4-[(7-(benzofuran-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ8.77-7.38 (m, 12H), 4.99-3.16 (m, 7H),1.44-1.27 (m, 3H). MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₄N₅O₄: 494.18. found494.24. HPLC retention time: 1.35 minutes (column A).

Example 108

Example 108, was prepared from Precursor 5n and 2-benzofuranyl boronicacid to provide(S)-1-picolinoyl-3-methyl-4-[(7-(benzofuran-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₄N₅O₄: 494.18. found 494.23. HPLCretention time: 1.37 minutes (column A).

Example 127

Example 127, was prepared from Precursor 5i and the benzothiophen-2-ylboronic acid to provide(R)-1-benzoyl-3-Methyl-4-[7-(benzothiophen-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₉H₂₅N₄O₃S: 509.16. found 509.21. HPLCretention time: 1.42 minutes (column A).

Example 128

Example 128, was prepared from Precursor 5i and the thiophen-2-ylboronic acid to provide(R)-1-benzoyl-3-Methyl-4-[(7-(thiophen-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₄O₃S: 459.15. found 459.27. HPLCretention time: 1.22 minutes (column A).

Example 129

Example 129, was prepared from Precursor 5i and the thiophen-3-ylboronic acid to provide(R)-1-benzoyl-3-Methyl-4-[7-(thiophen-3-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₄O₃S: 459.15. found 459.34. HPLCretention time: 1.31 minutes (column A).

Example 130

Example 130, was prepared from Precursor 5i and the2,5-dimethyl-isoxazol-4-yl boronic acid to provide(R)-1-benzoyl-3-Methyl-4-[7-(2,5-dimethyl-isoxazol-4-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₆N₅O₄: 472.20. found 472.28. HPLCretention time: 1.14 minutes (column A).

Example 132

Example 132, was prepared from Precursor 5p and the2-methylcarbonyl-thiophen-5-yl boronic acid to provide1-benzoyl-4-[(7-(2-methylcarbonyl-thiophen-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₃N₄O₄S: 487.14. found 487.20. HPLCretention time: 1.14 minutes (column A).

Example 133

Example 133, was prepared from Precursor 5p and the2-carbonyl-thiophen-5-yl boronic acid to provide1-benzoyl-4-[7-(2-carbonyl-thiophen-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₁N₄O₄S: 473.13. found 473.11. HPLCretention time: 1.14 minutes (column A).

Example 134

Example 134, was prepared from Precursor 5p and the4-methyl-thiophen-2-yl boronic acid to provide1-benzoyl-4-[(7-(4-methyl-thiophen-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₄O₃S: 459.15. found 459.08. HPLCretention time: 1.26 minutes (column G).

Example 152

Preparation of Example 152

To a mixture of acid precursor 16 (30 mg, 68 mol), 3-aminopyridine (26mg, 0.27 mmol) and DMAP (50 mg, 0.41 mmol) was added THF (2 ml), andthen EDC (60 mg, 0.31 mmol). The reaction mixture was stirred at ambienttemperature for 16 hours. The LC/MS analysis indicated that the majorproduct was the activated ester. The reaction mixture was then addedinto a DMF (2 ml) solution of 3-aminopyridine (400 mg, 4.25 mmol) andstirred at ambient temperature for 16 hours. After addition of MeOH (4ml), the reaction mixture was purified by preparative reverse phase HPLCto give the TFA salt of the title compound using the method: Start %B=30, Final % B=75, Gradient time=25 min, Flow Rate=25 ml/min, Column:YMC C18 Sum 20×100 mm, Fraction Collection: 10.41-11.08 min. ¹H NMR:(DMSO-d₆) δ 13.04 (s, 1H), 11.17 (s, 1H), 9.17 (s, 1H), 8.53 (s, 1H),8.35 (m, 3H), 7.44 (b s, 6H), 3.75-3.37 (b m, 8H); LC/MS: (ES+) m/z(M+H)⁺ =517, 519; HPLC R_(t)=1.653.

Example 143 Prep of Example 143

To a mixture of precursor 5q (31 mg, 65 μmol) and Pd(PPh₃)₄ (20 mg, 17μmol) was added 1,4-dioxane (1 ml) and ii (30 mg, 78 μmol). The reactionmixture was heated in a sealed tube at 145° C. for 4 hours. Aftercooling to ambient temperature, the reaction mixture was added MeOH (4ml) and then filtered. The filtrate was purified by preparative reversephase HPLC to give the TFA salt of the title compound using the method:Start % B=25, Final % B=90, Gradient time=20 min, Flow Rate=25 ml/min,Column: YMC C18 5 um 20×100 mm, Fraction Collection: 11.14-11.92 min. ¹HNMR: (DMSO-d₆) δ 12.71 (s, 1H), 9.01 (s, 1H), 8.36 (s, 1H), 8.27 (s,1H), 8.08 (s, 1H), 7.44 (b s, 5H), 7.44 (b s, 2H), 3.75-3.37 (b m, 8H);LC/MS: (ES+) m/z (M+H)⁺ =490, 492; HPLC R_(t)=2.250.

Example 149

Preparation of Example 49

To a suspension of compound of Example 143 (12 mg, 24 μmol) in sulfuricacid (5%, 2 ml), was charged sodium nitrite (22 mg, 0.32 mol) at 0° C.The reaction mixture was stirred at 0° C. for 30 minutes and then atambient temperature for 1 hour. After addition of MeOH (4 ml), thereaction mixture was purified by preparative reverse phase HPLC to givea TFA solvate of title compound using the method: Start % B=20, Final %B=85, Gradient time=15 min, Flow Rate=25 ml/min, Column: YMC C18 Sum20×100 mm, Fraction Collection: 10.67-11.36 min. ¹H NMR: (DMSO-d₆) δ12.62 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H),7.44 (b s, 5H), 3.80-3.30 (b m, 8H); LC/MS: (ES+) m/z (M+H)⁺ =491, 493;HPLC R_(t)=2.193.

Example 144

Preparation of Example 144

To a mixture of precursor 5q (50 mg, 105 μmol) and Pd(PPh₃)₄ (50 mg, 43μmol) was added 1,4-dioxane (1 ml) and iii (77 mg, 210 μmol). Thereaction mixture was heated in a sealed tube at 145° C. for 16 hours.After cooling to ambient temperature, the reaction mixture was addedMeOH (4 ml) and then filtered. The filtrate was purified by reversephase HPLC to give the TFA salt of the title compound of using themethod: Start % B=15, Final % B=100, Gradient time=20 min, Flow Rate=25ml/min, Column: YMC C18 Sum 20×100 mm, Fraction Collection: 11.80-12.31min. ¹H NMR: (CD₃OD) δ 9.32 (s, 1H), 9.25 (s, 2H), 8.50 (s, 1H), 8.44(s, 1H), 7.47 (b s, 5H), 4.00-3.44 (b m, 8H); LC/MS: (ES+) m/z (M+H)⁺=475, 477; HPLC R_(t)=1.833.

Example 87

Preparation of Example 87,1-benzoyl-4-[(4-methoxy-7-(2-hydroxycarbonyl-furan-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine:A mixture of the compound of Example 85 (19 mg), NaClO₂ (9.2 mg) in amixed solution of CH₃CN (3 mL) and water (0.5 mL) was stirred at roomtemperature for 24 hours. After the reaction was quenched by 1N NaOHsolution (1 ml), the mixture was extracted with diethyl ether (3×10 mL).The aqueous phase was acidified with 1N HCl to give a yellow solidprecipitate (5 mg) which was the product shown. MS m/z: (M+H)⁺ Calc'dfor C₂₆H₂₃N₆O₇: 503.16. found 503.19. HPLC retention time: 1.37 minutes(column A).

General Procedure of Converting —NH₂ Group to —NHCOR Group

Preparation of Example 99,1-(benzoyl)-4-[(4-methoxy-7-(2-acetylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine:1-(benzoyl)-4-[(4-methoxy-7-(2-amino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine(4 mg) and acetic anhydride (20 mg) were dissolved in pyridine (0.5 ml).The reaction was stirred for three hours at room temperature. Afterreaction was quenched with MeOH (1 ml), solvents were concentrated togive a residue which was purified using a Shimadzu automated preparativeHPLC System to provide 3.0 mg of the desired compound,1-(benzoyl)-4-[(4-methoxy-7-(2-acetylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ9.58 (s, 1H), 9.25 (s, 1H), 8.45 (s, 1H), 8.10(s, 1H), 7.49 (m, 5H), 4.12 (s, 3H), 3.84-3.35 (m, 8H), 2.27 (s, 3H). MSm/z: (M+H)⁺ Calc'd for C₂₇H₂₆N₇O₅: 528.20. found 528.22. HPLC retentiontime: 1.33 minutes (column A).

General Procedure of Converting —NH₂ Group to —OH Group

Preparation of Example 97,1-(benzoyl)-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine:1-(benzoyl)-4-[(4-methoxy-7-(2-amino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine(15 mg) and NaNO₂ (10 mg) was added into a H₂SO₄ solution (0.1 ml ofconcentrated H₂SO₄ diluted with 0.3 ml of water). The reaction wasstirred at room temperature for one hour. Then, the reaction mixture wasneutralized with a saturated Na₂CO₃ solution (10 ml). The solvents wereconcentrated to give a residue which was purified using a Shimadzuautomated preparative HPLC System to provide 4.2 mg of the desiredcompound,1-(benzoyl)-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.¹H NMR (500 MHz, CD₃OD) δ8.55 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 8.01(s, 1H), 7.49 (m, 5H), 4.12 (s, 3H), 3.84-3.64 (m, 8H). MS m/z: (M+H)⁺Calc'd for C₂₅H₂₃N₆O₅: 487.17. found 487.22. HPLC retention time: 1.13minutes (column A).

This general procedure is applied to prepare examples 121, 122,123,124,155, 157, and 162.

Example 121

Example 121,(R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₆O₄: 471.18. found 471.17. HPLCretention time: 1.39 minutes (column G).

Example 121-2

Example 121-2,(R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(2-hydroxyl-4-oxo-pyrazin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazinewas isolated during the preparation of Example 121. MS m/z: (M+H)⁺Calc'd for C₂₅H₂₃N₆O₅: 487.17. found 487.17. HPLC retention time: 1.08minutes (column G).

Example 122

Example 122,(R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(2-hydroxyl-pyridin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₄N₅O₄: 470.18. found 470.17. HPLCretention time: 1.03 minutes (column G).

Example 123

Example 123,(R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(2-hydroxyl-pyridin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₄N₅O₄: 470.18. found 470.14. HPLCretention time: 1.28 minutes (column G).

Example 124

Example 124,(R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(5-hydroxyl-pyridin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₄N₅O₄: 470.18. found 470.13. HPLCretention time: 1.21 minutes (column G).

Preparation of Example 138

Preparation of Example 138,1-(benzoyl)-4-[(4-methoxy-7-(1-methylpyrazin-2-on-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine:1-(benzoyl)-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine(6 mg), MeI (5 mg) and K₂CO₃ (4 mg) were dissolved in acetone (5 ml).The reaction was stirred for four hours at room temperature. After solidwas filtered away, the mother liquid was concentrated to give a residuewhich was purified using a Shimadzu automated preparative HPLC System toprovide 3.0 mg of the desired compound,1-(benzoyl)-4-[(4-methoxy-7-(1-methylpyrazin-2-on-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₅N₆O₅: 501.19. found 501.14. HPLCretention time: 1.08 minutes (column G).

Example 139

Precursor 4i was dissolved in DMF (2 ml), and to whichN-benzoyl-(R)-methylpiperazine hydrochloride (0.092 g, 0.45 mmol) and3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT, 0.180 g,0.60 mmol) were added, followed by N,N-diisopropylethylamine (0.15 ml,0.87 mmol). The reaction mixture was stirred for 2 h at r.t., and thenthe volatile evaporated under high vacuum. Water was added to themixture to induce precipitation, and the solids were filtered and driedin vacuo. Purification of the crude solid by preparative thin layerchromatography (5% MeOH/CH₂Cl₂), and subsequent washing with ether gavethe title compound; ¹H NMR: (CDCl₃) δ 8.78 (s, 1H), 8.32 (s, 1H), 8.28(s, 1H) 7.84 (s, 1H), 7.44 (b s, 5H), 6.56 (s, 1H), 5.00-3.00 (b m, 7H),1.45-1.20 (b s, 3H); LC/MS: (ES+) m/z (M+H)⁺ =521, 523; HPLCR_(t)=1.677.

Preparation of N-Linked Azaindole Heterocylic Derivatives from theCorresponding Bromide or Chloride. An Example of a Typical Procedure:

A general reaction condition is shown with the preparation of example187. Other analogs, examples 188-193, were preparaed via the samereaction condition.

Example 187

Preparation of Compound of Example 187

Precursor 5b (30 mg), 1,2,4-triazole (145 mg), Cu (4.4 mg) and K2CO3(9.6 mg) were combined in a sealed tube which was degassed before beingsealed. The mixture was heated to 160° C. for 8 hours. After beingallowed to cool down to ambient temperature, the mixture was dilutedwith MeOH (14 ml) and dichloromethane (7 ml). After filtration, thefiltrate was concentrated to give a residue which was purified using aShimadzu automated preparative HPLC System to provide 12.9 mg of thedesired compound 187,1-benzoyl-4-[(4-methoxy-7-(1,2,4-triazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₃H₂₂N₇O₄: 460.17. found 460.33. HPLCretention time: 1.45 minutes (column J)

Example 188 and Example 188A

Example 188 and 188A, were prepared according to the general methoddescribed above starting from Precursor 5z and 1,2,3-triazole to provideExample 188 and Example 188A.

Precursor 5z (0.050 g), 0.050 g Cu powder, 0.025 g K2CO3 and 6equivalents of 1,2,3 triazole were heated at 150 C for 16 hrs. Thereaction was allow to cool to ambient temperature and was dissolved inMeOH and purified by Prep HPLC as described above in the general methodsto provide Example 188 (0.0237 g brown solid, yield 44%) and the theother isomer Example 188a.

Example 188,1-benzoyl-4-[(4-methoxy-7-(1,2,3-triazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₃H₂₂N₇O₄: 460.17. found 460.34. HPLCretention time: 1.50 minutes (column J); 1.29 minutes (column L). ¹H NMR(500 MHz, CD₃OD) δ8.86 (s, 1H), 8.34 (s, 1H), 7.97 (m, 2H), 7.48 (b,5H), 4.08 (s, 3H), 3.89-3.56 (m, 8H).

Example 188A,1-benzoyl-4-[(4-methoxy-7-(1,2,3-triazol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₃H₂₂N₇O₄: 460.17. found 460.34. HPLCretention time: 1.39 minutes (column J)¹H NMR (500 MHz, CD₃OD) δ8.32 (s,1H), 7.76 (s, 1H), 7.45 (b, 7H), 4.07 (s, 3H), 3.80-3.30 (m, 8H).

Example 189

Example 189, was prepared from Precursor 5b and pyrazole to provide1-benzoyl-4-[(4-methoxy-7-(1-pyrazolyl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₃N₆O₄: 459.18. found 459.01. HPLCretention time: 0.92 minutes (column G).

Example 190

Example 190, was prepared from Precursor 5b and 3-methylpyrazole toprovide1-benzoyl-4-[(4-methoxy-7-(3-methylpyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₅N₆O₄: 473.19. found 473.09. HPLCretention time: 1.49 minutes (column G).

Example 191

Example 191, was prepared from Precursor 5b and 4-methylpyrazole toprovide1-benzoyl-4-[(4-methoxy-7-(4-methylpyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₅N₆O₄: 473.19. found 473.09. HPLCretention time: 1.52 minutes (column G).

Example 192

Example 192, was prepared from Precursor 5b and3-trifluoromethylpyrazole to provide1-benzoyl-4-[(4-methoxy-7-(3-trifluoromethylpyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₂F₃N₆O₄: 527.17. found 527.09. HPLCretention time: 1.64 minutes (column G).

Example 193

Example 193, was prepared from Precursor 5b and imidazole to provide1-benzoyl-4-[(4-methoxy-7-(1-imidazolyl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₃N₆O₄: 459.18. found 459.26. HPLCretention time: 1.22 minutes (column G).

Example 140

The title compound was prepared according to general proceduresdescribed before (Sn-coupling). H NMR: 8.41 (m, 1H); 8.33 (m, 1H); 8.16(m, 1H); 7.53 (m, 1H); 7.47 (bs, 5H); 3.97-3.54 (m, 8H). LC/MS: (ES⁺)m/z (m+H)⁺ =448, Rt=1.28 min.

Example 141

The title compound was prepared according to general proceduresdescribed before (Sn-coupling). ¹H-NMR: 9.71-9.70 (m, 1H); 8.80-8.79 (m,1H); 8.66-8.42 (m, 2H); 8.41-8.35 (m, 2H); 7.99-7.92 (m, 1H), 7.69-7.53(m, 1H); 7.48-7.44 (m, 1H); 5.05-3.15 (m, 8H). LC/MS: (ES⁺) m/z (m+H)⁺=474. Rt=1.26 min.

Example 144

Preparation of Example 144

To a mixture of precursor 5q (50 mg, 105 μmol) and Pd(PPh₃)₄ (50 mg, 43μmol) was added 1,4-dioxane (1 ml) and iii (77 mg, 210 μmol). Thereaction mixture was heated in a sealed tube at 145° C. for 16 hours.After cooling to ambient temperature, the reaction mixture was addedMeOH (4 ml) and then filtered. The filtrate was purified by reversephase HPLC to give the TFA salt of the title compound of using themethod: Start % B=15, Final % B=100, Gradient time=20 min, Flow Rate=25ml/min, Column: YMC C18 Sum 20×100 mm, Fraction Collection: 11.80-12.31min. ¹H NMR: (CD₃OD) δ 9.32 (s, 1H), 9.25 (s, 2H), 8.50 (s, 1H), 8.44(s, 1H), 7.47 (b s, 5H), 4.00-3.44 (b m, 8H); LC/MS: (ES+) m/z (M+H)⁺=475, 477; HPLC R_(t)=1.833.

Example 145

The title compound was prepared following the procedure described beforefor example 146 and precursor 4k. ¹H NMR: 8.35-8.33 (m, 2H); 8.11 (s,1H); 7.89 (s, 1H); 7.43 (bs, 5H); 3.89-3.49 (m, 8H). LC/MS: (ES⁺) m/z(M+H)⁺ =448. Rt=1.18 min.

Example 146

Precursor 4m (0.26 mmol) was dissolved in DMF (1 mL) and treated withN-benzoylpiperazine hydrochloride (59 mg, 0.26 mmol), DEBPT (79 mg, 0.26mmol) and Hunig's base (90 μL, 0.52 mmol) and the reaction mixture wasstirred at rt for 18 h. The solvent was removed in vacuum and theresidue was purified by reverse phase preparative HPLC. The fractionsshowing the right LC/MS:(ES⁺) m/z (M+H)⁺ =449 were collected,concentrated and purified again using a preparative TLC (5% MeOH/CH₂Cl₂)to afford the title compound as a white solid. ¹H-NMR (500 MHz, CDCl₃) δ10.7 (s, 1H), 9.00 (s, 1H), 8.54 (s, 1H), 8.39 (s, 1H), 7.45 (m, 5H),3.9-3.5 (bm, 8H).

Example 148

The title compound was prepared from precursor 4n using the samecoupling conditions described for the last step of the preparation ofprecursor 5i. ¹H NMR: 8.82 (m, 1H); 8.48-8.45 (m, 1H); 8.37-8.33 (m,1H); 8.26-8.23 (m, 1H); 7.47 (bs, 5H); 3.97-3.54 (m, 8H). LC/MS: (ES⁺)m/z (m+H)⁺ =447 Rt=0.94 min.

Example 151

Example 151, was prepared from Precursor 51 and the thiazol-5-ylstannane to provide1-picolinoyl-4-[(4-methoxy-7-(thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₃H₂₁N₆O₄S: 477.13. found 477.13. HPLCretention time: 0.94 minutes (column G).

Example 154

The title compound was prepared according to general proceduresdescribed before (Sn-coupling). ¹H-NMR: 9.23-9.22 (m, 1H); 8.83-8.81 (m,1H); 8.43 (m, 1H); 8.36 (m, 1H); 7.75-7.73 (m, 1H), 7.44 (bs, 5H);3.85-3.49 (m, 8H). LC/MS: (ES⁺) m/z (M+H)⁺ =459. Rt=1.39 min.

Example 155

Example 155,1-(benzoyl)-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₆O₅: 487.17. found 487.14. HPLCretention time: 1.30 minutes (column G).

Example 157

Example 157,(R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(5-hydroxyl-pyrazin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₆O₄: 471.18. found 471.16. HPLCretention time: 1.09 minutes (column G).

Example 161

Example 161 was prepared from precursor 5p and3-phenyl-5-tributylstannyl-1,2,3-triazole using the general tin couplingprocedure provided earlier: ¹H NMR (500 MHz, DMSO) δ 9.67 (s, 1H), 8.81(s, 1H), 8.72 (d, J=5.4 Hz, 1H), 8.25 (d, J=6.1 Hz, 1H), 8.00 (dd,J=8.2, 1.8 Hz, 1H), 7.68 (dd, J=8.2, 7.4 Hz, 2H), 7.60 (tt, J=7.4, 1.8Hz, 2H), 7.48 (br s, 5H), 4.04-3.46 (m, 8H). MS m/z: (M+H)⁺ calcd forC₂₈H₂₄N₂O₃: 506.19. found 506.15. HPLC retention time: 1.21 minutes(XTERRA C18 S7 3.0×50 mm))

Example 162

Example 162,(R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(2-hydroxyl-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₃N₆O₄: 471.18. found 471.13. HPLCretention time: 0.95 minutes (column G).

Example 163

To a solution of precursor 5q (50 mg, 0.11 mmol) in DMF (1 ml) was addedCuCN (30 mg, 0.335 mmol). The reaction mixture was heated at 170° C. for30 min. After cooling to ambient temperature, the reaction mixture wasdiluted with MeOH (15 ml), filtered under gravity, and the filtrateevaporated in vacuo to afforded a brownish residue which is acyanoprecursor. To the residue in DMF (1 ml) was added sodium azide (61mg, 0.95 mmol) and ammonium chloride (50 mg, 0.95 mmol). The mixture washeated at 90° C. for one hour. The reaction mixture was then dilutedwith MeOH (4 ml), filtered, and the filtrate purified by preparativereverse phase HPLC using the method: Start % B=20, Final % B=80,Gradient time=15 min, Flow Rate=40 ml/min, Column: XTERRA C18 5 um30×100 mm, Fraction Collection: 11.26-11.71 min. The material washomogenous by ¹H NMR and HPLC, although the mass spectrum indicated anextra peak at (M+H)⁺ =431; ¹H NMR: (CD₃OD) 8.41 (s, 1H), 8.12 (s, 1H),7.47 (b s, 5H), 3.97-3.47 (b m, 8H); LC/MS: (ES+) m/z (M+H)⁺ =465, 467;HPLC R_(t)=1.937

Example 164

Example 164, was prepared from Precursor 5a and the4-hydroxycarbonylphenyl boronic acid to provide1-benzoyl-4-[(7-(4-hydroxycarbonylphenyl)-4-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₅N₄O₅: 497.18. found 497.22. HPLCretention time: 1.20 minutes (column C).

Example 165

Compound of Example 165 was prepared in a similar manner to compound ofExample 143 starting with precursor 5r, but at 125° C. for 22 hours andpurification by preparative thin layer chromatography (4% MeOH/CH₂Cl₂).¹H NMR: (CDCl₃) δ 11.85 (s, 1H), 9.91 (d, J=1.6 Hz, 1H), 8.70 (d, J=2.6Hz, 1H), 8.65 (dd, J=1.6, 2.6 Hz, 1H), 8.52 (s, 1H), 8.35 (d, J=3.1 Hz,1H), 3.73 (b m, 2H), 3.56 (b m, 4H), 3.53 (b m, 2H), 1.48 (s, 9H);LC/MS: (ES+) m/z (M+H)⁺ =471, 473; HPLC R_(t)=1.690.

Example 167

Precursor 4m (0.098 mmol) was dissolved in DMF (1 mL) and treated withN-[5-(2-Bromofuroyl)]piperazine hydrochloride (30 mg, 0.098 mmol), DEBPT(60 mg, 0.19 mmol) and Hunig's base (70 μL, 0.19 mmol) and the reactionmixture was stirred at rt for 18 h. The solvent was removed in vacuumand the residue was purified by reverse phase preparative HPLC. Thefractions showing the right LC/MS:(ES⁺) m/z (M+H)⁺ =518,520 werecollected, concentrated and purified again using a preparative TLC (5%MeOH/CH₂Cl₂) to afford the title compound as a white solid. ¹H-NMR (500MHz, CDCl₃) δ 10.7 (s, 1H), 9.00 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H),7.06 (d, J=3.4 Hz, 1H), 6.46 06 (d, J=3.4 Hz, 1H), 3.90-3.66 (bm, 8H).

Example 168

Example 168,1-benzoyl-3-(R)-methyl-4-[(7-(2-thienylcarbonyl)-4-azaindol-3-yl)-oxoacetyl]piperazine,was prepared from a reaction1-benzoyl-3-(R)-methyl-4-[(7-(methoxymethylamino)carbonyl)-4-azaindol-3-yl)-oxoacetyl]piperazineand 2-thienyl lithium by using the same procedure for the preapartion of1-64,1-benzoyl-3-(R)-methyl-4-[(7-(2-propynyl)carbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₃N₄O₄S: 487.14. found 487.11. HPLCretention time: 1.31 minutes (column A).

General Procedure for the Preparation of Piperazine Amides orCarbamides:

The free nitrogen atom of piperazine could be masked as amides orcarbamides via reactions of piperazine with acyl halides, acyl acids oracyl halo formates, which are shown in the following schemes 80 and 81.

Example 195-199 were prepared via a procedure demonstrated in Scheme 80.The typical procedure is presented in the synthesis of Example 195.

Example 195

Example 195: Precursor 5u (40 mg), pyrazine carbonyl chloride (50 mg)and I-Pr₂NEt (0.2 g) were combined in 1 ml of THF. After the reactionwas stirred at room temperature for 16 h, the mixture was concentratedin vacuo to give a residue which was purified using a Shimadzu automatedpreparative HPLC System to provide the desired compound 195 (4.7 mg). MSm/z: (M+H)⁺ Calc'd for C₂₃H₂₁N₈O₄: 473.17. found 473.42. HPLC retentiontime: 1.14 minutes (column C).

Example 196

Example 196, was prepared from Precursor 5u and 4-isoxazole carbonylchloride. MS m/z: (M+H)⁺ Calc'd for C₂₂H₂₀N₂O₅: 462.15. found 462.41.HPLC retention time: 1.09 minutes (column C).

Example 197

Example 197, was prepared from Precursor 5u and4-(1,2,3-thiodiazole)-carbonyl chloride. MS m/z: (M+H)⁺ Calc'd forC₂₁H₁₉N₈O₄S: 479.12. found 479.31. HPLC retention time: 1.17 minutes(column C).

Example 198

Example 198, was prepared from Precursor 5u and5-(3-amino-1,2,4-triazole)-carbonyl chloride. MS m/z: (M+H)⁺ Calc'd forC₂₁H₂₁N₁₀O₄: 477.17. found 477.36. HPLC retention time: 0.97 minutes(column C).

Example 199

Example 199, was prepared from Precursor 5u and propanyl chloro formate.MS m/z: (M+H)⁺ Calc'd for C₂₂H₂₅N₆O₅: 453.19. found 453.17. HPLCretention time: 1.53 minutes (column M).

Example 200-201 were prepared via a procedure demonstrated in Scheme 81.The typical procedure is presented in the synthesis of Example 200.

Example 200

Example 200: 3-methyl-2-picolinic acid (140 mg), EDAC (190 mg)pentafluorophenol (180 mg) were combined in DMF, and, the reaction wasstirred for 12 hours. Precursor 3u was then added and resulted mixturewas stirred at room temperature for another 16 hours. Solvents wereremoved in vacuo to give a residue which was purified using a Shimadzuautomated preparative HPLC System to provide the desired compound 200(28 mg). MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₄N₇O₄: 486.19. found 486.14.HPLC retention time: 1.08 minutes (column G).

Example 201

Example 201, was prepared from Precursor 5u and 6-methyl-2-picolinicacid. MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₄N₇O₄: 486.19. found 486.28. HPLCretention time: 1.44 minutes (column G).

Example 202

Example 202, was prepared from Precursor 5p and the ethyl pyrazol-5-ylstannane carboxylate to provide5-{3-[2-(4-Benzoyl-piperazin-1-yl)-2-oxo-acetyl]-1H-pyrrolo[3,2-b]pyridin-7-yl}-2H-pyrazole-3-carboxylicacid ethyl ester. MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₅N₆O₅: 501.18. found501.13. HPLC retention time: 1.14 minutes (column G).

Example 203

Example 202, was prepared from Precursor 5p and the benzofuran-2-ylstannane to provide1-(7-benzofuran-2-yl-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-(4-benzoyl-piperazin-1-yl)-ethane-1,2-dione.MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₁N₄O₄: 479.16. found 479.07. HPLCretention time: 1.31 minutes (column G).

Example 204

Example 204, was prepared from Precursor 5p and the oxazol-2-yl stannaneto provide1-benzoyl-4-[(7-(oxazol-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine. MSm/z: (M+H)⁺ Calc'd for C₂₃H₂₀N₅O₄: 430.14. found 430.07. HPLC retentiontime: 2.08 minutes (column E, 10 minute gradient).

Example 205 and Example 206

Example 205 and 206. In a sealedtube-(4-benzoyl-piperazin-1-yl)-2-(7-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione(30 mg, 0.076 mmol), 1H-1,2,3-triazole (160 mg, 2.3 mmol), Cu (0) (10mg, 0.16 mmol) and K₂CO₃ (11 mg, 0.080 mmol) were heated at 160° C. for16 h. The reaction mixture was diluted with MeOH, filtered throughcelite and concentrated. The reaction mixture was diluted with MeOH,filtered through celite and concentrated. The residue was purified bypreparative HPLC to provide1-(4-benzoyl-piperazin-1-yl)-2-(7-[1,2,3]triazol-2-yl-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione:¹H NMR (300 MHz, CD₃OD) δ 8.79 (d, J=6.6 Hz, 1H), 8.79 (s, 1H), 8.48 (d,J=6.6 Hz, 1H), 8.40 (s, 2H), 7.48 (br s, 5H), 4.00-3.55 (m, 8H). MS m/z(M+H)⁺ calcd for C₂₂H₂₀N₇O₃: 430.15. found 430.29. HPLC retention time0.91 min (Column G); and1-(4-benzoyl-piperazin-1-yl)-2-(7-[1,2,3]triazol-1-yl-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione:¹H NMR (300 MHz, CD₃OD) δ 8.97 (d, J=61.2 Hz, 1H), 8.70 (d, J=5.6 Hz,1H), 8.48 (s, 1H), 8.06 (d, J=1.2 Hz, 1H), 7.80 (d, J=5.6 Hz, 1H), 7.47(br s, 5H), 4.00-3.45 (m, 8H). MS m/z (M+H)⁺ calcd for C₂₂H₂₀N₇O₃:430.15. found 430.29. HPLC retention time 0.90 min (Column G).

Example 207

Example 207, was prepared as in Example 205 from Precursor 5p and1,2,4-triazole to provide1-(4-benzoyl-piperazin-1-yl)-2-(7-[1,2,4]triazol-1-yl-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione.¹H NMR (300 MHz, CD₃OD) δ 9.73 (s, 1H), 8.82 (d, J=6.6 Hz, 1H), 8.77 (s,1H), 8.55 (s, 1H), 8.32 (d, J=6.6 Hz, 1H), 7.48 (br s, 5H), 4.00-3.45(m, 8H). MS m/z (M+H)⁺ calcd for C₂₂H₂₀N₇O₃: 430.15. found 430.27. HPLCretention time 0.87 min (Column G).

Example 208

Example 208, was prepared as in Example 205 from Precursor 5p andpyrazole to provide1-(4-Benzoyl-piperazin-1-yl)-2-(7-pyrazol-1-yl-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione.¹H NMR (300 MHz, CD₃OD) δ 8.87 (d, J=2.7 Hz, 1H), 8.70 (s, 1H), 8.68 (d,J=6.6 Hz, 1H), 8.18 (d, J=1.5 Hz, 1H), 8.14 (d, J=6.6 Hz, 1H), 7.48 (brs, 5H), 6.85 (dd, J=2.7, 1.5 Hz, 1H), 4.00-3.50 (m, 8H). MS m/z (M+H)⁺calcd for C₂₃H₂₁N₆O₃: 429.16. found 429.23. HPLC retention time 0.87 min(Column G).

Example 209

The compound of Example 209 was prepared according to the general methoddescribed above starting from Precursor 5i and pyrazol-3-carboxylicethyl ester-5-tributyltin prepared as described in the followingreference: Heterocycles, 1992, 33(2), 813-18. After cooling to ambienttemperature, the reaction mixture was concentrated in vacuum. Theresidue was filtered through filter paper and washed with methanol. Theresulting yellow solid was dried in air to provide Compound X; ¹H NMR(500 MHz, CDCl₃): 8.33 (s, 1H); 8.31 (s, 1H); 7.66 (s, 1H); 7.46-7.39(m, 5H); 4.47-4.42 (q, 2H); 3.98-3.45 (m, 8H); 1.43-1.40 (t, 3H). LC/MS:(ES⁺) m/z (M+H)⁺ =519. Rt=1.43 min.

Examples 210-213

General Procedure for the Preparation of Examples 210-213

The compound of Example 209 was treated with an excess (>5 eq.) of thecorresponding amine and stirred in a sealed tube at ambient temperatureor 70° C. (R═NH₂) for 20 hr. The resulting solution was concentrated ona rotary evaporator and purified by reverse phase preparative HPLC.

Examples 210 and 214

Compounds of Example 210 and 214 were prepared from compound of Example209 and ammonium hydroxide following the procedure described above. X1a:¹H NMR (500 MHz, CD₃OD₃): 8.40-8.37 (m, 1H); 8.28-8.27 (m, 1H);7.58-7.39 (m, 6H); 3.97-3.43 (m, 8H). LC/MS: (ES⁺) m/z (M+H)⁺ =490.Rt=1.14 min. X1b: 8.43 (s, 1H); 8.29 (s, 1H); 7.56 (s, 1H); 7.45-7.55(m, 5H); 3.99-3.45 (m, 8H). LC/MS: (ES⁺) m/z (M+H)⁺=491. Rt=1.12 min.

Example 211

The compound od Example 211 was prepared from the compound of Example209 and methylamine following the procedure described above. ¹H NMR (500MHz, CD₃OD₃): 8.43 (s, 1H); 8.31 (s, 1H); 7.49 (bs, 5H); 7.45 (s, 1H)3.97-3.48 (m, 8H); 2.97 (s, 3H). LC/MS: (ES⁺) m/z (M+H)⁺ =504. Rt=1.31min.

Example 212

The compound of example 212 was prepared from the compound of example209 and dimethylamine following the procedure described above. LC/MS:(ES⁺) m/z (M+H)⁺=518. Rt=122 min.

Compound 213

The compound of Example 213 was prepared from the compound of Example209 and N-aminoethylmorpholine following the procedure described above.¹H NMR (500 MHz, CD₃OD₃): 8.41 (s, 1H); 8.31 (s, 1H); 7.52-7.49 (m, 6H);4.19-3.20 (m, 20H); LC/MS: (ES⁺) m/z (M+H)⁺ =603. Rt=1.03 min.

Compounds of Examples 215-222

General Procedure for the Preparation of Compounds of Examples 215-222

A mixture of precursor 5i, 30 equivalents of the corresponding amine, 1equivalent of copper powder and 1 equivalent of potassium carbonate washeated at 160° C. for 4-7 hr in a sealed tube. The reaction was cooledto room temperature and filtered through filter paper. The filtrate wasdiluted with methanol and purified by preparative HPLC.

Example 215

Example 215 was prepared from precursor 5i and 1,2,4-triazole followingthe procedure described above. ¹H NMR (500 MHz, CDCl₃): 11.15 (bs, 1H);9.28 (s, 1H); 8.33-8.34 (m, 1H); 8.22 (s, 1H); 8.10 (s, 1H); 7.46-7.42(m, 5H); 3.90-3.48 (m, 8H). LC/MS: (ES⁺) m/z (M+H)⁺ =448. Rt=1.21 min.

Example 216

Example 216 was prepared from precursor 5i and 1,2,3-triazole followingthe procedure described above. ¹H NMR (500 MHz, CDCl₃): 11.16 (bs, 1H);8.75 (s, 1H); 8.37-8.37 (s, 1H); 8.15 (s, 1H); 7.92 (s, 1H); 7.43 (bs,5H); 3.99-3.48 (m, 8H). LC/MS: (ES⁺) m/z (M+H)⁺=448. Rt=1.28 min.

Example 217

Example 217 was prepared from precursor 5i and 1,2,3-triazole followingthe procedure described above. ¹H NMR (500 MHz, CDCl₃): 11.12 (bs, 1H);8.78-8.77 (m, 1H); 8.37-8.36 (m, 1H); 8.02-8.0 (m, 2H); 7.45-7.41 (m,5H); 4.11-3.45 (m, 8H). LC/MS: (ES⁺) m/z (M+H)⁺ =448. Rt=1.03 min.

Example 218

Example 218 was prepared from precursor 5i and imidazole following theprocedure described above. ¹H NMR (500 MHz, CDCl₃): 13.35 (bs, 1H); 9.49(s, 1H); 8.35-8.30 (m, 1H); 8.20 (s, 1H); 7.97 (s, 1H); 7.56-7.53 (m,1H); 7.46-7.41 (m, 5H); 3.98-3.40 (m, 8H). LC/MS: (ES⁺) m/z (M+H)⁺ =447.Rt=1.25 min.

Example 219

Example 219 was prepared from precursor 5i and pyrazole following theprocedure described above. ¹H NMR (500 MHz, CDCl₃): 11.52 (bs, 1H);8.65-8.64 (m, 1H); 8.27-8.26 (m, 1H); 8.05-8.04 (m, 1H); 7.81-7.80 (m,1H); 7.50-7.35 (m, 5H); 6.54-6.53 (m, 1H); 4.01-3.47 (m, 8H). LC/MS:(ES⁺) m/z (M+H)⁺ =447. Rt=1.25 min.

Example 220

Example 220 was prepared from precursor 5i and pyrrole following theprocedure described above. ¹H NMR (300 MHz, CD₃OD₃): 8.33-8.29 (m, 2H);7.49-7.40 (m, 5H); 7.38-7.37 (m, 2H); 6.42-6.41 (m, 2H); 3.91-3.40 (m,8H). LC/MS: (ES⁺) m/z (M+H)⁺=446. Rt=1.34 min.

Example 221

Example 221 was prepared from precursor 5i and pyrrolidine following theprocedure described above. ¹H NMR (300 MHz, CD₃OD₃): 8.37 (s, 1H);7.61-7.59 (m, 1H); 7.51-7.38 (m, 5H); 4.08-3.23 (m, 12H); 2.25-2.15 (m,4H). LC/MS: (ES⁺) m/z (M+H)⁺=450. Rt=0.89 min.

Example 222

Compound of example 222 was prepared from precursor 5i and morpholinefollowing the procedure described above. ¹H NMR (300 MHz, CD₃OD₃): 8.38(s, 1H); 7.86-7.84 (m, 1H); 4.14-3.25 (m, 16H). LC/MS: (ES⁺) m/z(M+H)⁺=466. Rt=0.988 min.

Preparation of Precursor 5w:

To a mixture of 2u (2.0 g, 7.3 mmol) and CuCN (1.0 g, 11 mmol) was addedDMF (20 ml). The reaction mixture was heated at 150° C. for 1 hour.After cooling to room temperature, the reaction mixture was added NaOMe(20 ml, 25 wt. % solution in MeOH), and was heated at 110° C. for 10minutes. After cooling to room temperature, the reaction mixture waspoured into an aqueous solution of ammonium acetate (sat. 500 ml). Theresulting mixture was filtered through a short Celite® pad. The filtratewas extracted with EtOAc (500 ml×4). The combined extracts were driedover MgSO₄ and evaporated in vacuo to give a brownish residue, which wastriturated with MeOH (5 ml×3) to provide precursor 2v as a yellow solid(317 mg, 25%). The structure was supported by NOE experiments. ¹H NMR:(DMSO-d₆) 12.47 (s, 1H), 8.03 (s, 1H), 7.65 (t, J=2.8, 1H), 6.70 (dd,J=2.8, 1.8, 1H), 4.08 (s, 3H); LC/MS: (ES+) m/z (M+H)⁺ =174; HPLC(alternate conditions B, column G) R_(t)=1.320.

Preparation of Precursor 3h:

To 1-ethyl-3-methylimidazolium chloride (85 mg, 0.58 mmol) in a cappedvial was quickly added aluminum chloride (231 mg, 1.73 mmol). Themixture was vigorously stirred at room temperature until the formationof the ionic liquid. After cooling to room temperature, the ionic liquidwas added compound 2v (50 mg, 0.29 mmol) and ethyl chlorooxoacetate (0.2ml, 1.79 mmol). The reaction mixture was stirred at room temperature forthree hours, cooled to 0° C. and quenched by carefully adding ice-water(15 ml). The precipitates were filtered, washed with water (5 ml×3) anddried in vacuo to give 3 h as a grayish yellow solid (50 mg, 63%). ¹HNMR: (DMSO-d₆) 13.73 (s, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 4.35 (q,J=7.0, 2H), 4.06 (s, 3H), 1.29 (t, J=7.0, 3H); LC/MS: (ES+) m/z (M+H)⁺=274; HPLC (alternate conditions B, column G) R_(t)=1.527.

Preparation of Precursor 4p:

To a mixture of 3 h (200 mg, 0.73 mmol) in MeOH (1 ml) was added NaOH(2.5 ml, 1N aqueous). The reaction mixture was stirred at roomtemperature for 30 minutes, and then acidified with hydrochloric acid(1N, ˜3 ml) to pH about 2. The solid was filtered, washed with water (5ml×4), and dried in vacuo to give 4p as a brownish solid (160 mg, 89%).Compound 4p was used directly in the following reaction without furtherpurification. LC/MS: (ES+) m/z (M+H)⁺ =246; HPLC (alternate conditionsB, column G) R_(t)=0.777.

Preparation of Precursor 5w:

To a mixture of 4p (160 mg, 0.65 mmol), DEPBT (390 mg, 1.31 mmol) andbenzoylpiperazine hydrochloride (222 mg, 0.98 mmol) was added DMF (2 ml)and N,N-diisopropylethylamine (1.2 ml, 6.9 mmol). The reaction mixturewas stirred at room temperature for 16 hours, and concentrated to removemost of the solvent. The residue was diluted with MeOH (10 ml) and thenfiltered. The filtrate was purified by preparative reverse phase HPLCusing the method: Start % B=15, Final % B=70, Gradient time=30 min, FlowRate=40 ml/min, Wavelength=220 nm, Column: XTERRA C18 5 μm 30×100 mm,A=10% MeOH, −90% H₂O—0.1% TFA, B=90% MeOH—10% H₂O—0.1% TFA, FractionCollection: 14.03-15.43 min. The structure was supported by NOEexperiments. ¹H NMR: (DMSO-d₆) 13.66 (s, 1H), 8.45 (s, 1H), 8.25 (s,1H), 7.45 (s, 5H), 4.07 (s, 3H), 3.80-3.40 (b m, 8H); LC/MS: (ES+) m/z(M+H)⁺ =418 HPLC (alternate conditions B, column G) R_(t)=1.447.

Preparation of Example 223

To a mixture of 5w (15 mg, 0.036 mmol), NaN₃ (24 mg, 0.36 mmol), andNH₄Cl (19 mg, 0.36 mmol) was added DMF (1 ml). The reaction mixture washeated at 100° C. for three hours. After cooling to room temperature,the reaction mixture was added MeOH (4 ml) and then filtered. Thefiltrate was purified by preparative reverse phase HPLC using themethod: Start % B=15, Final % B=75, Gradient time=15 min, Flow Rate=40ml/min, Wavelength=220 nm, Column: XTERRA C18 5 μm 30×100 mm, A=10%MeOH, −90% H₂O—0.1% TFA, B=90% MeOH—10% H₂O—0.1% TFA, FractionCollection: 8.48-9.78 min. ¹H NMR: (DMSO-d₆) 12.68 (b s, 1H), 8.26 (s,1H), 8.24 (s, 1H), 7.46 (s, 5H), 4.09 (s, 3H), 3.86-3.30 (b m,overlapping with broad water peak, 8H), one exchangeable proton was notobserved due to the presence of water in the sample. LC/MS: (ES+) m/z(M+H)⁺ =461 HPLC (alternate conditions B, column G) R_(t)=1.392.

Preparation of Examples 224 and 225

To the mixture of 5w (10 mg, 0.022 mmol) in MeOH (0.2 ml) and benzene(0.4 ml) was added TMSCHN₂ (0.4 ml, 0.1 M*). The reaction mixture wasstirred at room temperature for 1.5 hours, followed by purification onpreparative TLC (1×20×20 cm, 500 microns) with 10% MeOH/CH₂Cl₂ to givethe two compounds as white solids. Example 224 (2.7 mg, 26%); ¹H NMR:(DMSO-d₆) 12.60 (b s, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 7.46 (s, 5H),4.50 (s, 3H), 4.15 (s, 3H), 3.80-3.30 (b m, 8H); LC/MS: (ES+) m/z (M+H)⁺=475, HPLC (alternate conditions B, column G) R_(t)=1.672. Example 225(1.4 mg, 13%), ¹H NMR: (DMSO-d₆) 12.40 (b s, 1H), 8.22 (s, 1H), 8.20 (s,1H), 7.46 (s, 5H), 4.52 (s, 3H), 4.04 (s, 3H), 3.80-3.30 (b m, 8H);LC/MS: (ES+) m/z (M+H)⁺ =475, HPLC (alternate conditions B, column G)R_(t)=1.373. These two structures were further supported by nitrogenHMBC analysis.

*TMSCHN₂ (0.1 M) was prepared by diluting commercially available TMSCHN₂(0.2 ml, 2.0 M) with hexane (3.8 ml).

Example 226

Reaction Scheme for Prep of Example 226

Preparation of Example 226

To a mixture of 5w (85 mg, 0.204 mmol) and hydroxylamine hydrochloride(22 mg, 0.305 mmol) in anhydrous ethanol (3 ml, 200 proof) was addedtriethylamine (60 μl, 0.4 mmol). The reaction mixture was heated in acapped vial at 100° C. for 6 hours. Removal of solvent gave precursor 5xas a white solid, to which was added triethyl orthoformate (3 ml). Themixture was then heated in a capped vial at 100° C. for 12 hours. Afterremoval of most of the excess triethyl orthoformate, the residue wasdiluted with MeOH (6 ml), followed by filtration. The filtrate waspurified by preparative reverse phase HPLC using the method: Start %B=30, Final % B=50, Gradient time=20 min, Flow Rate=40 ml/min, Column:XTERRA C18 5 μm 30×100 mm, Fraction Collection: 7.57-7.98 min. ¹H NMR:(DMSO-d₆) 12.41 (s, 1H), 9.87 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.45(s, 5H), 4.06 (s, 3H), 3.68-3.20 (b m, overlapping with broad waterpeak, 8H); The following HPLC conditions for the analytical LCMS wereused: Column: Xterra C18 S7 3×50 mm; Gradient Time=3 min; Flow rate=4ml/min. LC/MS: (ES+) m/z (M+H)⁺ =461 HPLC R_(t)=1.390. Product from asimilar run provided the following 1H NMR spectra (methanol-d6) δ 9.32(s, 1H), 8.28 (s, 2H), 7.83 (s, 1H), 7.45 (narrow multiplet, 6H), 4.05(s, 3H), 3.80 (bm, 4H), 3.56 (bm, 4H).

Examples 227 to 229

Examples 227 to 230 (Table 2-1) were prepared analogously to Example 194except that the appropriate substituted piperazine was utilized. Thepreparation of the appropriate substituted piperazines is described forprecursors 17a-d or in reference 90b.

General Procedures for the Preparation of Pyrazoles

3-Substituted pyrazoles can be prepared via the following routes:

Alkyne (1 eq.) was dissolved in a 2M solution of diazomethane (5-10 eq.)in hexane and resulting mixture was heated to 110-115° C. for 12 hours.After reaction was quenched with MeOH, removal of solvents provided aresidue which was used in the next step without any purification.

Methyl ketone (1 eq.) was added into a solution of dimethoxy-DMF (5-10eq.) in DMF and the resulting mixture was heated to 110-115° C. for 12hours. Solvents were then removed under vacuum to provide a residue.

The above residue was mixed with hydrazine (5-10 eq.) in ethanol and thereaction was kept in refluxing for 12 hours. Removal of solvents invacco gave a residue, which was carried onto further reactions withoutpurification.

Hydrazine (10-20 eq.) was added into a solution of alkenone or alkenal(1 eq.) in THF and the resulting mixture was heated to 110-115° C. for12 hours. After the mixture cooled down to room temperature, an excessof NiO2-2H2O (5-10 eq.) was then added into the reaction mixture and thereaction was stirred at room temperature for another 12 hours. Insolublematerials were then filtered away and concentration under vacuumprovided a residue that was used in the further reactions withoutpurification.

TABLE I-5 Preparation of Pyrazoles HPLC R_(f) (column)/ Method MS (M +H)⁺ or Compound^(#) Structure Used (M + Na)⁺ Pyrazole-001

P-A 0.35 min (column L) Pyrazole-002

P-A 0.59 min (column L) Pyrazole-003

P-A 1.07 min (column L)/ MS (M + H)⁺: Calc'd 139.12 Found 139.18Pyrazole-004

P-A, P- B, P-C 0.53 min (column L) Pyrazole-005

P-B 0.48 min (column L) Pyrazole-006

P-A 0.63 min (column L) Pyrazole-007

P-A 0.21 min (cloumn G) Pyrazole-008

P-A 0.81 min (column L)/ MS (M + H)⁺: Calc'd 197.13 Found 197.18Pyrazole-009

P-A Pyrazole-010

P-A 0.34 min (column L) Pyrazole-011

P-A 0.47 min (column L)/ MS (M + H)⁺: Calc'd 155.08 Found 155.06Pyrazole-012

P-A 0.38 min (column G) Pyrazole-013

P-A Pyrazole-014

P-A Pyrazole-015

P-A 0.26 min (column L)/ MS (M + Na)⁺: Calc'd 149.07 Found 149.11Pyrazole-016

P-A 0.31 min (column L)/ MS (M + H)⁺: Calc'd 141.10 Found 141.17Pyrazole-017

P-A 0.27 min (column L)/ MS (M + Na)⁺: Calc'd 149.07 Found 149.13Pyrazole-018

P-A 0.22 min (column L) Pyrazole-019

P-A 0.61 min (column L)/ MS (M +Na)⁺: Calc'd 175.08 Found 175.14Pyrazole-020

P-A 0.79 min (column L)/ MS (M + Na)⁺: Calc'd 189.10 Found 189.17Pyrazole-021

P-A 0.59 min (column L)/ MS (M + H)⁺: Calc'd 141.10 Found 141.18Pyrazole-022

P-A 0.22 (column L) Pyrazole-023

P-A 0.34 min (column L)/ MS (M + Na)⁺: Calc'd 193.10 Found 193.14Pyrazole-024

P-A 1.05 min (column L)/ MS (M + H)⁺: Calc'd 228.08 Found 228.14

General Procedure Si—Cu

Silicon Masked General Procedure for Attaching Pyrazoles, Imidazoles andTriazoles with Melting-Points Higher than 160° C. to C-7 Position ofAzaindoles:

In cases where the meltingpoints of the nitrogen heterocycle to beattached to the azaindole have melting points higher than 160° C., anexcess of the heterocycle (usually greater than 3 equivalents) is heatedwith a larger excess of hexamethydisilazane or chloro trimethylsilane(>10 equivalents) at temperatures up to 140° C. for approximately 12 h.The excess silylating reagent is removed in vacuo and the mixture iscombined with the azaindole halide and the copper catalyzed reaction isconducted as below.

A mixture of halo-indole or halo-azaindole intermediate, 1-2 equivalentsof copper powder, with 1 equivalent preferred for the 4-F,6-azaindoleseries and 2 equivalents for the 4-methoxy,6-azaindole series; 1-2equivalents of potassium carbonate, and the the corresponding silylatedheterocyclic reagent as prepared above, was heated at 135-160° C. for 4to 9 hours, with 5 hours at 160° C. preferred for the 4-F,6-azaindoleseries and 7 hours at 135° C. preferred for the 4-methoxy,6-azaindoleseries. The reaction mixture was cooled to room temperature and filteredthrough filter paper. The filtrate was diluted with methanol andpurified either by preparative HPLC or silica gel. In many cases nochromatography is necessary, the product can be obtained bycrystallization with methanol.

TABLE I-6 N-containing Heterocycles Applied under General ProcedureSi—Cu (Silicon-Masking Conditions) Entry N-Containing Heterocycle HM-01

HM-02

HM-03

HM-04

HM-05

HM-06

HM-07

Examples 230 Through Example 258, were Prepared Using the SameConditions and Method Used for Synthesizing Example 187 Example 230

Example 230, was prepared according to the general method describedabove starting from Precursor 5z and Pyrazole-001 to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-ethyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₉N₆O₄: 501.23. found 501.17. HPLCretention time: 2.30 minutes (column G, flow rate 4 ml/min, gradienttime 3 min)

Example 231

Example 231, was prepared according to the general method describedabove starting from Precursor 5z and Pyrazole-002 to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-propyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₈H₃₁N₆O₄: 515.24. found 515.19. HPLCretention time: 2.47 minutes (column G, flow rate 4 ml/min, gradienttime 3 min)

Example 232

Example 232, was prepared according to the general method describedabove starting from Precursor 5z and Pyrazole-006 to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-cycloputyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₉H₃₁N₆O₄: 527.24. found 527.16. HPLCretention time: 2.53 minutes (column G, flow rate 4 ml/min, gradienttime 3 min)

Example 233

Example 233, was prepared according to the general method describedabove starting from Precursor 5z and Pyrazole-012 to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-ethoxy-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₉N₆O₅: 517.22. found 517.17. HPLCretention time: 2.26 minutes (column G, flow rate 4 ml/min, gradienttime 3 min).

Example 234

Example 234, was prepared according to the general method describedabove starting from Precursor 5z and Pyrazole-011 to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-(2-hydroxylcarbonylethan-1-yl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₉N₆O₄: 545.21. found 545.15. HPLCretention time: 2.08 minutes (column G, flow rate 4 ml/min, gradienttime 3 min)

Example 235

Example 235, was prepared according to the general method describedabove starting from Precursor 5z and Pyrazole-009 to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-(1-hydroxylethyl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₉N₆O₅: 517.22. found 517.15. HPLCretention time: 1.43 minutes (column G).

Examples 236 and 237

Examples 236 and 237, were prepared according to the general methoddescribed above starting from Precursor 5z and Pyrazole-007 to provideExample 236,(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-hydroxylmethyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazineand Example 237,(R)-1-benzoyl-3-methyl-4-[(4-methoxy-7-(4-hydroxylmethyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.

Example 236,(R)-1-benzoyl-3-methyl-4-[(4-methoxy-7-(3-hydroxylmethyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine:MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₇N₆O₅: 503.20. found 503.20. HPLCretention time: 1.87 minutes (column G, flow rate 4 ml/min, gradienttime 3 min).

Example 237,(R)-1-benzoyl-3-methyl-4-[(4-methoxy-7-(4-hydroxylmethyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine:MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₇N₆O₅: 503.20. found 503.25. HPLCretention time: 1.31 minutes (column G, flow rate 4 ml/min, gradienttime 3 min).

Example 238

Example 238, was prepared according to the general method describedabove starting from Precursor 5z and Pyrazole-013 to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-methoxymethyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₉N₆O₅: 517.22. found 517.23. HPLCretention time: 1.95 minutes (column G, flow rate 4 ml/min, gradienttime 3 min).

Example 239

Example 239, was prepared according to the general method describedabove starting from Precursor 5z and Pyrazole-014 to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-(N,N-dimethylamino)methyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₈H₃₂N₇O₄: 530.25. found 530.25. HPLCretention time: 1.45 minutes (column G, flow rate 4 ml/min, gradienttime 3 min)

Examples 190 and 240

Examples 190 and 240, were prepared according to the general methoddescribed above starting from Precursor 5b and 3-methylpyrazole toprovide Example 190 and Example 240.

Example 240,1-benzoyl-4-[(4-methoxy-7-(5-methyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₅N₆O₄: 473.19. found 473.19. HPLCretention time: 1.35 minutes (column G).

Example 190,1-benzoyl-4-[(4-methoxy-7-(3-methyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₅N₆O₄: 473.19. found 473.17. HPLCretention time: 1.50 minutes (column G).

Examples 241 and 242

Examples 241 and 242, were prepared according to the general methoddescribed above starting from Precursor 5z and 3-methylpyrazole.

Example 241,(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-methyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₆N₆O₄: 487.21. found 486.20. HPLCretention time: 1.54 minutes (column G).

Example 242,(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(5-methyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₇N₆O₄: 487.21. found 486.20. HPLCretention time: 1.41 minutes (column G).

Example 243

Example 243, was prepared according to the general method describedabove starting from Precursor 5z and 3-t-butylpyrazole to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-t-butyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₉H₃₀N₆O₄: 529.26. found 529.29. HPLCretention time: 1.86 minutes (column G).

Example 244

Example 244, was prepared according to the general method describedabove starting from Precursor 5z and 3-trifluoromethylpyrazole toprovide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-trifluoromethyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₄F₃N₆O₄: 541.18. found 541.25. HPLCretention time: 1.71 minutes (column G).

Example 245

Example 245, was prepared according to the general method describedabove starting from Precursor 5z and 1,2,4-triazole to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(1,2,4-triazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₄N₇O₄: 474.19. found 474.23. HPLCretention time: 1.29 minutes (column G).

Example 246

Example 246, was prepared according to the general method describedabove starting from Precursor 5z and 1,2,3-benzotriazole to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(1,2,3-benzotriazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₆N₇O₄: 524.20. found 524.27. HPLCretention time: 1.68 minutes (column G).

Example 247

Example 247, was prepared according to the general method describedabove starting from Precursor 5b and Pyrazole-010 to provide1-benzoyl-4-[(4-methoxy-7-(3-(1-hydroxyl-1-methylethyl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₉N₆O₅: 517.22. found 517.37. HPLCretention time: 1.38 minutes (column L).

Example 248

Example 248, was prepared according to the general method describedabove starting from Precursor 5b and Pyrazole-008 to provide1-benzoyl-4-[(4-methoxy-7-(3-(3-hydroxylethyl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₇N₆O₅: 503.20. found 503.27. HPLCretention time: 1.16 minutes (column L).

Example 249

Example 249, was prepared according to the general method describedabove starting from Precursor 5b and Pyrazole-004 to provide1-benzoyl-4-[(4-methoxy-7-(3-iso-propyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₉N₆O₄: 501.23. found 501.34. HPLCretention time: 1.74 minutes (column L).

Example 250

Example 250, was prepared according to the general method describedabove starting from Precursor 5b and Pyrazole-003 to provide1-benzoyl-4-[(4-methoxy-7-(3-n-pentyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₉H₃₃N₆O₄: 529.26. found 529.34. HPLCretention time: 1.96 minutes (column L).

Examples 251 and App 252

Examples 251 and 252, were prepared according to the general methoddescribed above starting from Precursor 5b and 3-aminopyrazole.

Example 251,1-benzoyl-4-[(4-methoxy-7-(3-amino-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₄N₇O₄: 474.29. found 474.24. HPLCretention time: 1.58 minutes (column G).

Example 252,1-benzoyl-4-[(4-methoxy-7-(5-amino-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₄N₇O₄: 474.29. found 474.22. HPLCretention time: 1.59 minutes (column G).

Examples 253 and 254

Examples 253 and 254, were prepared according to the general methoddescribed above starting from Precursor 5z and 3-aminopyrazole.

Example 253,(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-amino-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₆N₇O₄: 488.20; found 488.25. HPLCretention time: 1.65 minutes (column G, flow rate=4 ml/min, gradienttime=3 min)

Example 254,(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(5-amino-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₆N₇O₄: 488.20. found 488.25. HPLCretention time: 1.74 minutes (column G, flow rate=4 ml/min, gradienttime=3 min)

Examples 255 and 256

Examples 255 and 256, were prepared according to the general methoddescribed above starting from Precursor 5z and 1,2,3-triazole. Precursor5z (0.056 g), 0.056 g Cu powder, 0.025 g K2CO3 and 10 equivalents of1,2,3 triazole were heated at 155-170 C for 4 hrs. The reaction wasallowed to cool to ambient temperature and the residue was dissolved inMeOH and purified by Prep HPLC. as described above in the generalmethods to provide Example 255 (0.020 g) as a brown solid, yield 34% andthe other isomer Example 256.

Example 255,(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(1,2,3-triazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₄N₇O₄: 474.19. found 474.21. HPLCretention time: 1.84 minutes (column G, flow rate=4 ml/min, gradienttime=3 min)¹H NMR (500 MHz, CD₃OD) δ8.85 (s, 1H), 8.32 (ss, 1H), 7.94(m, 2H), 7.48 (m, 5H), 4.07 (ss, 3H), 4.00-3.00 (m, 7H), 1.33 (m, 3H).

Example 256,(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(1,2,3-triazol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₄N₇O₄: 474.19. found 474.21. HPLCretention time: 1.66 minutes (column G, flow rate=4 ml/min, gradienttime=3 min)¹H NMR (500 MHz, CD₃OD) δ8.33 (ss, 1H), 8.13 (s, 1H), 7.46(m, 7H), 4.07 (ss, 3H), 4.00-3.00 (m, 7H), 1.32 (m, 3H).

Example 257

Example 257, was prepared according to the general method describedabove starting from Precursor 5z and 3-hydroxylpyrazole to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-hydroxylpyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₅N₆O₅: 489.19. found 489.15. HPLCretention time: 1.38 minutes (column G).

Example 258

Example 258, was prepared according to the general method describedabove starting from Precursor 5z and 3-amino-1,2,4-triazole to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-amino-1,2,4-triazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₅N₈O₄: 489.20. found 489.24. HPLCretention time: 1.69 minutes (column G).

Examples 259 Through 265, were Prepared According to the GnereralProcedure Si—Cu (Silicon-Masking Conditions) Described Above Example 259

Example 259, was prepared according to the general method Si—Cu(Silicon-Masking) described above starting from Precursor 5z and3-methylcarbonylpyrazole to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-methylcarbonyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₇N₆O₅: 515.20. found 515.15. HPLCretention time: 1.51 minutes (column G).

Example 260

Example 260, was prepared according to the general method Si—Cu(Silicon-Masking) described above starting from Precursor 5z and3-phenylpyrazole to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-phenyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₃₁H₂₉N₆O₄: 549.23. found 549.18. HPLCretention time: 1.82 minutes (column G).

Example 261

Example 261, was prepared according to the general method Si—Cu(Silicon-Masking) described above starting from Precursor 5z and3-(3-pyridinemethylamino)-1,2,4-triazole to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-(3-pyridinemethylamino)-1,2,4-triazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₃₀H₃₀N₉O₄: 580.24. found 580.14. HPLCretention time: 1.15 minutes (column G).

Example 262

Example 262, was prepared according to the general method Si—Cu(Silicon-Masking) described above starting from Precursor 5z and3-acetylaminopyrazole to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-acetylamino-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₈N₇O₅: 530.22. found 530.15. HPLCretention time: 1.41 minutes (column G).

Example 263

Example 263 was prepared according to the general method Si—Cu(Silicon-Masking) described above starting from Precursor 5z and3-(2-methylpyridin-5-yl)pyrazole to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-(2-methylpyridin-5-yl)pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₃₁H₃₀N₇O₄: 564.24. found 564.26. HPLCretention time: 1.22 minutes (column C).

Example 264

Example 264 was prepared according to the general method Si—Cu(Silicon-Masking) described above starting from Precursor 5b and3-(2-methylpyridin-5-yl)pyrazole to provide1-benzoyl-4-[(4-methoxy-7-(3-(2-methylpyridin-5-yl)pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₃₀H₂₈N₇O₄: 550.22. found 550.26. HPLCretention time: 1.20 minutes (column C).

Example 265

Example 265 was prepared according to the general method Si—Cu(Silicon-Masking) described above starting from Precursor 5z and3-(1,2,4-triazol-1-yl)ethyl-pyrazole to provide(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-(1,2,4-triazol-1-yl)ethyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₉H₃₀N₉O₄: 568.24. found 568.13. HPLCretention time: 1.44 minutes (column G).

Examples 266 to 270, were Prepared According to a Procedure Analogous tothe Procedure Used Synthesize Example 15 Example 266

Example 266, was prepared according to the general method describedabove starting from Precursor 5z and 2-amino-pyrazin-5-yl tributyltin,to provide(R)-1-benzoyl-2-methyl-4-[(7-(2-amino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₆N₇O₄: 500.20. found 500.26. HPLCretention time: 1.11 minutes (column G).

Example 267

Example 267, was prepared according to the general method describedabove starting from Precursor 5za and 2-amino-pyrazin-5-yl tributyltin,to provide(R)-1-picolinoyl-2-methyl-4-[(7-(2-amino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₅N₈O₄: 501.20. found 501.30. HPLCretention time: 1.04 minutes (column J)

Example 268

Example 268, was prepared according to the general method describedabove starting from Precursor 5xa and 4-methylsulfonylphenyl boronicacid, to provide(R)-1-picolinoyl-2-methyl-4-[(7-(4-methylsulfonyl-phenyl-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₈N₅O₆S: 562.18. found 562.19. HPLCretention time: 0.86 minutes (column G).

Example 269

Example 269, was prepared according to the general method describedabove starting from Precursor 5xa and tri-butylstannyl pyrazine, toprovide(R)-1-picolinoyl-2-methyl-4[(7-pyrazinyl-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₄N₇O₄: 486.19. found 486.32. HPLCretention time: 1.07 minutes (column G).

Example 270

Example 270, was prepared according to the general method describedabove starting from Precursor 5y and tri-butylstannyl pyrazine, toprovide(R)-1-nicotinoyl-2-methyl-4-[(7-pyrazinyl-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₄N₇O₄: 486.19. found 486.10. HPLCretention time: 0.96 minutes (column L).

Examples 271 through 272, were prepared using the “General Procedure ofConverting —NH₂ Group to —OH Group”, Examplified by the preparation ofExample 97 Example 271

Example 271, was prepared according to the general method describedabove starting from Example 266 to provide(R)-1-benzoyl-2-methyl-4-[(7-(5-hydroxyl-pyrazin-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₅N₆O₅: 501.19. found 501.21. HPLCretention time: 1.08 minutes (column G).

Example 272

Example 272, was prepared according to the general method describedabove starting from Example 267 to provide(R)-1-picolinoyl-2-methyl-4-[(7-(5-hydroxyl-pyrazin-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₄N₇O₅: 502.18. found 502.19. HPLCretention time: 0.88 minutes (column G).

Example 273

Example 273, was prepared from Precursor 5b and1H-[1,2,4]-triazole-3-carboxylic acid ethylamide to provide1-benzoyl-4-[(4-methoxy-7-(3-ethylaminocarbonyl-1,2,4-triazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₇N₈O₅: 531.21. found 531.21. HPLCretention time: 1.75 minutes (column G). ¹H NMR (500 MHz, CD₃OD) δ9.35(s, 1H), 8.34 (s, 1H), 7.86 (s, 1H), 7.48 (b, 5H), 4.06 (s, 3H),4.00-3.49 (m, 10H), 1.30 (t, 3H, J=7.5 Hz).

Example 274

Example 274, was prepared from Precursor 5b and1H-[1,2,4]-triazole-3-carboxylic acid methylamide to provide1-benzoyl-4-[(4-methoxy-7-(3-methylaminocarbonyl-1,2,4-triazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₅H₂₅N₈O₅: 517.19. found 517.18. HPLCretention time: 1.67 minutes (column G). ¹H NMR (500 MHz, CD₃OD) δ9.36(s, 1H), 8.35 (s, 1H), 7.88 (s, 1H), 7.48 (b, 5H), 4.06 (s, 3H),3.80-3.60 (m, 8H), 3.02 (s, 3H).

Example 275

Example 275, was prepared from Precursor 5b and1H-[1,2,4]-triazole-3-carboxylic acid dimethylamide to provide1-benzoyl-4-[(4-methoxy-7-(3-dimethylaminocarbonyl-1,2,4-triazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₇N₈O₅: 531.21. found 531.28. HPLCretention time: 1.71 minutes (column G).

Example 276

Example 276, was prepared from Precursor 5b and 1H-pyrazole-3-carboxylicacid methylamide to provide1-benzoyl-4-[(4-methoxy-7-(3-methylaminocarbonyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₆N₇O₅: 516.20. found 516.27. HPLCretention time: 1.86 minutes (column G).

Example 277

Example 277, was prepared from Precursor 5b and1-(1H-pyrazol-3-yl)-propan-2-ol to provide1-benzoyl-4-[(4-methoxy-7-(3-(2-hydroxylpropyl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₇H₂₉N₆O₅: 517.22. found 517.38. HPLCretention time: 1.42 minutes (column L).

Example 278

Example 278, was prepared from Precursor 5b and3-cyclohex-1-enyl-1H-pyrazole to provide1-benzoyl-4-[(4-methoxy-7-(3-(cyclohexen-1-yl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₃₀H₃₁N₆O₄: 539.24. found 539.26. HPLCretention time: 1.96 minutes (column L).

Example 279

Example 279, was prepared from Precursor 5b and4-(1H-pyrazol-3-yl)-butyronitrile to provide1-benzoyl-4-[(4-methoxy-7-(3-(3-cyano-propan-1-yl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₈H₂₈N₇O₄: 526.22. found 526.35. HPLCretention time: 1.51 minutes (column L).

Example 280

Example 280, was prepared from Precursor 5b and4-(1H-pyrazol-3-ylmethyl)-thiomorpholine 1,1-dioxide to provide1-benzoyl-4-[(4-methoxy-7-(3-(1,1-dioxo-thiomorpholin-4-yl)methyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₉H₃₂N₇O₆S: 606.21. found 606.34. HPLCretention time: 1.01 minutes (column L).

Example 281

Example 281, was prepared from Precursor 5b and 3-isobutyl-1H-pyrazoleto provide1-benzoyl-4-[(4-methoxy-7-(3-isobutyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₈H₃₁N₆O₄: 515.24. found 515.35. HPLCretention time: 1.90 minutes (column L).

Example 282

Example-282, was prepared from Precursor 5b and1-(1H-pyrazol-3-yl)-cyclopentanol to provide1-benzoyl-4-[(4-methoxy-7-(3-(1-hydroxy-cyclopentyl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₉H₃₁N₆O₅: 543.24. found 543.43. HPLCretention time: 1.51 minutes (column L).

Example 283

Example 283, was prepared from Precursor 5b andmethyl-(1H-pyrazol-3-ylmethyl)-amine to provide1-benzoyl-4-[(4-methoxy-7-(3-methylaminomethyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₈N₇O₄: 502.22. found 502.31. HPLCretention time: 1.51 minutes (column L).

Example 284

Example 284, was prepared from Precursor 5b and2-methyl-1-(1H-pyrazol-3-yl)-propan-1-ol to provide1-benzoyl-4-[(4-methoxy-7-(3-(1-hydroxy-2-methyl-propyl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.MS m/z: (M+H)⁺ Calc'd for C₂₈H₃₁N₆O₅: 531.24. found 531.43. HPLCretention time: 1.63 minutes (column L).

Example 285

Example 285, was prepared according to the general method describedabove starting from Precursor 5b and Pyrazole-025 to provide1-benzoyl-4-[(4-methoxy-7-(3-(4-ethoxycarbonyl-phenyl)oxymethyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₃₄H₃₃N₆O₇: 637.24. found 637.34. HPLCretention time: 1.87 minutes (column G). ¹H NMR (500 MHz, CDCl₃) 68.61(s, 1H), 8.16 (s, 1H), 8.02 (d, 2H, J=15 Hz), 7.76 (s, 1H), 7.43 (b,5H), 7.05 (d, 2H, J=14.5 Hz), 6.60 (s, 1H), 5.29 (s, 2H), 4.33 (q, 2H,J=12 Hz), 4.03 (s, 3H), 3.80-3.57 (m, 8H), 1.38 (t, 3H, J=12.0 Hz).

Example 286

Example 286, was prepared according to the general method describedabove starting from Precursor 5b and 3-(toluene-4-sulfonyl)-1H-pyrazoleto provide1-benzoyl-4-[(4-methoxy-7-(3-(toluene-4-sulfonyl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₃₁H₂₉N₆O₆S: 613.19. found 613.28. HPLCretention time: 1.69 minutes (column G). ¹H NMR (500 MHz, CDCl₃) 68.64(s, 1H), 8.21 (s, 1H), 7.94 (d, 2H, J=8.00 Hz), 7.74 (s, 1H), 7.43 (b,5H), 7.34 (d, 2H, J=8.00 Hz), 6.94 (s, 1H), 4.04 (s, 3H), 4.00-3.40 (m,8H), 2.42 (s, 3H).

Example 287

Example 287, was prepared according to the general method describedabove starting from Precursor 5b and3-(3-trifluoromethyl-phenyl)-1H-pyrazole to provide1-benzoyl-4-[(4-methoxy-7-(3-(3-trifluoromethyl-phenyl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C_(3i)H₂₆F₃N₆O₄: 603.20. found 603.32. HPLCretention time: 1.94 minutes (column G). ¹H NMR (500 MHz, CDCl₃) δ 8.67(s, 1H), 8.26 (s, 1H), 8.09-7.42 (m, 10H), 6.87 (s, 1H), 4.01 (s, 3H),4.00-3.62 (m, 8H).

Example 288

Example 288, was prepared according to the general method describedabove starting from Precursor 5b and3-(4-trifluoromethyl-phenyl)-1H-pyrazole to provide1-benzoyl-4-[(4-methoxy-7-(3-(4-trifluoromethyl-phenyl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₃M₂₆F₃N₆O₄: 603.20. found 603.32. HPLCretention time: 1.96 minutes (column G). ¹H NMR (500 MHz, CDCl₃) δ 8.69(s, 1H), 8.26 (s, 1H), 8.09-7.43 (m, 10H), 6.87 (s, 1H), 4.01 (s, 3H),4.00-3.62 (m, 8H).

Example 289

Example 289, was prepared according to the general method describedabove starting from Precursor 5b and 3-propylsulfanyl-1H-[1,2,4]triazoleto provide1-benzoyl-4-[(4-methoxy-7-(3-propylsulfanyl-[1,2,4]triazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₈N₇O₄S: 534.19. found 534.32. HPLCretention time: 1.65 minutes (column G). ¹H NMR (500 MHz, CDCl₃) δ 9.09(s, 1H), 8.18 (s, 1H), 7.70 (s, 1H), 7.37 (m, 5H), 4.05 (s, 3H),3.90-3.30 (m, 8H), 3.18 (t, 2H, J=11.5 Hz), 1.74 (m, 2H), 1.02 (t, 3H,J=12.5 Hz).

Example 290

Example 290 (18 mg) was dissolved in 1 ml of AcOOH (37% in AcOH) at roomtemperature and the mixture was kept stirring for 10 hours. Removal ofsolvents under vacuum provided a reduce, which was purified usingShimadzu automated preparative HPLC System to provide Example 290,1-benzoyl-4-[(4-methoxy-7-(3-(propane-1-sulfonyl)-[1,2,4]triazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₆H₂₈H₇O₆S: 566.18. found 566.30. HPLCretention time: 1.44 minutes (column G). ¹H NMR (500 MHz, CDCl₃) δ 9.33(s, 1H), 8.24 (s, 1H), 7.80 (s, 1H), 7.43 (m, 5H), 4.08 (s, 3H),3.90-3.50 (m, 8H), 3.42 (t, 2H, J=8.00 Hz), 1.90 (m, 2H), 1.09 (t, 3H,J=7.50 Hz).

Example 291

Example 290, obtained from the previous stage, was dissolved in 5 ml ofMeONa (8 wt % in MeOH) at room temperature and the mixture was heated to90° C. for 10 hours to form 291,1-benzoyl-4-[(4-methoxy-7-(3-methoxy-[1,2,4]triazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₂₄H₂₄N₇O₅: 490.18. found 490.29. HPLCretention time: 1.36 minutes (column G).

Example 292

Example 288 (8 mg) was dissolved in 0.2 ml of concentrated at roomtemperature and the mixture was heated to 70° C. for 6 hours. Then themixture was quenched with water (2 ml) to form Example 292, which waspurified using Shimadzu automated preparative HPLC System (2.1 mg ofExample 292 obtained). Example 292,1-benzoyl-4-[(4-methoxy-7-(3-(4-hydroxylcarbonylphenyl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₃₁H₂₇N₆O₆: 579.20. found 579.28. HPLCretention time: 1.72 minutes (column G). ¹H NMR (500 MHz, CDCl₃) 68.71(s, 1H), 8.29 (s, 1H), 8.15 (d, 2H, J=8.00 Hz), 7.97 (d, 2H, J=8.00 Hz),7.80 (s, 1H), 7.45 (m, 5H), 6.90 (s, 1H), 4.05 (s, 3H), 4.02-3.49 (m,8H).

Example 293

Example 288 (8 mg) was dissolved in 0.2 ml of concentrated at roomtemperature and the mixture was heated to 70° C. for 6 hours. Then themixture was quenched with MeOH (2 ml) to form Example 293, which waspurified using Shimadzu automated preparative HPLC System (1.1 mg ofExample 293 obtained). Example 293,1-benzoyl-4-[(4-methoxy-7-(3-(4-methoxycarbonylphenyl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₃₂H₂₉N₆O₆: 593.21. found 593.32. HPLCretention time: 1.84 minutes (column G). ¹H NMR (500 MHz, CDCl₃) δ 8.74(s, 1H), 8.29 (s, 1H), 8.16 (d, 2H, J=8.00 Hz), 7.94 (d, 2H, J=8.00 Hz),7.79 (s, 1H), 7.44 (m, 5H), 6.89 (s, 1H), 4.05 (s, 3H), 3.96 (s, 3H),3.90-3.40 (m, 8H).

Example 294

Example 287 (6 mg) was dissolved in 0.2 ml of concentrated at roomtemperature and the mixture was heated to 70° C. for 6 hours. Then themixture was quenched with water (2 ml) to form Example 294, which waspurified using Shimadzu automated preparative HPLC System (2.7 mg ofExample 294 obtained). Example 294,1-benzoyl-4-[(4-methoxy-7-(3-(3-hydroxylcarbonylphenyl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;MS m/z: (M+H)⁺ Calc'd for C₃₁H₂₇N₆O₆: 579.20. found 579.28. HPLCretention time: 1.74 minutes (column G). ¹H NMR (500 MHz, CDCl₃) 68.76(s, 1H), 8.56 (s, 1H), 8.30 (s, 1H), 8.10 (m, 2H), 7.77 (m, 1H), 7.80(s, 1H), 7.45 (m, 5H), 6.87 (s, 1H), 4.04 (s, 3H), 4.00-3.40 (m, 8H).

Example 295

Example 136 (6 mg), succinic anhydride (20 mg) and DMAP (5 ml) weredissolved in 5 ml of anhydrous pyridine at room temperature and themixture was heated to reflux for 10 hours. Then the mixture was quenchedwith MeOH and solvents were removed under vacuum to provide a residue,which was purified using Shimadzu automated preparative HPLC System togive Example 295 (2.4 mg), 2,2-Dimethyl-succinic acid4-(1-{3-[2-(4-benzoyl-3-methyl-piperazin-1-yl)-2-oxo-acetyl]-4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl}-1H-pyrazol-3-ylmethyl)ester; MS m/z: (M+H)⁺ Calc'd for C₃₂H₃₅N₆O₈: 631.25. found 631.34. HPLCretention time: 1.64 minutes (column G).

Example 296

Example 111 (10 mg), trans-epoxysuccinyl chloride (20 mg) and Et₃N (0.2ml were dissolved in 2 ml of anhydrous THF at room temperature and themixture was kept stirring for 10 hours. Then the mixture was quenchedwith water and solvents were removed under vacuum to provide a residue,which was purified using Shimadzu automated preparative HPLC System togive Example 296 (2 mg),3-(6-{3-[2-(4-Benzoyl-2-methyl-piperazin-1-yl)-2-oxo-acetyl]-1H-pyrrolo[2,3-c]pyridin-7-yl}-pyrazin-2-ylcarbamoyl)-oxirane-2-carboxylicacid; MS m/z: (M+H)⁺ Calc'd for C₂₉H₂₆N₇O₇: 584.19. found 584.36. HPLCretention time: 1.44 minutes (column G).

Example 297

Example 112 (10 mg), trans-epoxysuccinyl chloride (20 mg) and Et₃N (0.2ml) were dissolved in 2 ml of anhydrous THF at room temperature and themixture was kept stirring for 10 hours. Then the mixture was quenchedwith water and solvents were removed under vacuum to provide a residue,which was purified using Shimadzu automated preparative HPLC System togive Example 297 (5 mg),3-(6-{3-[2-(4-Benzoyl-2-methyl-piperazin-1-yl)-2-oxo-acetyl]-1H-pyrrolo[2,3-c]pyridin-7-yl}-pyridin-2-ylcarbamoyl)-oxirane-2-carboxylicacid; MS m/z: (M+H)⁺ Calc'd for C₃₀H₂₇N₆O₇: 583.19. found 583.34. HPLCretention time: 1.31 minutes (column G).

Precursor 4P

Precursor 2p (200 mg, 1.0 mmol) was dissolved in trichloroaceticanhydride (1.2 mL) and heated at 80° C. for 3 h. MeOH (10 mL) was addedand the mixture was stirred at rt for 30 min. The volatiles were removedin vacuo. The residue was diluted with AcOEt (25 mL) and washed withwater (2×25 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated. The resulting crude oil was dissolved in DMF (1 mL) andtreated with a 2M solution of MeNH₂ in MeOH (2 mL). The reaction mixturewas stirred at rt for 18 h. LC/MS: (ES⁺) m/z (M+H)⁺ =234. The volatileswere removed in vacuo and the crude (134 mg) was taken to next stepwithout further purification.

Precursor 4P

Precursor 4p was prepared from precursor 2u following the proceduredescribed to prepare precursor 4m. LC/MS: (ES⁺) m/z (M+H)⁺ =306. Takento next step without further purification.

Example 298

Example 298 was prepared from precursor 4p by treatment with EDC (434mg, 2.3 mmol), HOBt (308 mg, 2.3 mmol) and benzoylpiperazine (304 mg,1.36 mmol) in DMF (2 mL). The mixture was stirred at rt for 18 h andthen concentrated in vacuo and purified using reverse phase HPCL toafford the title compound. LC/MS: (ES⁺) m/z (M+H)⁺ =478; rt=1.25 min.

Precursors 2V and 2VV

To a diethylether (10 mL) solution of trimethylsilyldiazomethane (2 M inhexane, 5.3 mL) was added n-BuLi (2.5 M in hexane, 4.2 mL) at 0° C.After stirring for 20 min, the resulting mixture was added into adiethylether (5 ml) solution of 4-fluoro-7-bromo-6-azaindole (340 mg,2.1 mmol). The reaction was stirred at 0° C. for 60 min and then,quenched with water (20 mL). The reaction mixture was extracted withethyl acetate (2×40 mL). The organic layers were combined, dried overMgSO₄, filtered and concentrated. The residue was triturated with ethylacetate. The solid was filtered and dried in air to give precursor 2v asa white solid (35 mg). ¹H NMR (300 MHz, CD₃OD): 8.43 (bs, 1H); 8.09-8.08(m, 1H); 7.64-7.63 (m, 1H); 6.72-6.71 (m, 1H). LC/MS: (ES⁺) m/z (M+H)⁺=204. Rt=0.50 min. The filtrate was concentrated and purified on silicagel column eluting with 5-10% of ethyl acetate/hexane to affordprecursor 2vv as a yellow solid (422 mg). ¹H NMR (300 MHz, CDCl₃):8.09-8.08 (m, 1H); 7.47-7.45 (m, 1H); 6.69-6.67 (m, 1H); 0.45 (s, 9H).LC/MS: (ES⁺) m/z (M+H)⁺ =276. Rt=1.39 min.

Precursor 4Q

Precursor 4q was prepared following the procedure described before forcompound 4m. LC/MS: (ES⁺) m/z (M+H)⁺ =276. Rt=0.42 min.

Example 299

The title compound was prepared following the coupling procedurepreviously described before for precursor 5a ¹H NMR (300 MHz, DMSO):8.44 (m, 1H); 8.33-8.31 (m, 2H); 7.44 (m, 5H); 3.87-3.40 (m, 8H). LC/MS:(ES⁺) m/z (M+H)⁺ =448. Rt=1.04 min.

N-Hydroxy-Acetamidine

Sodium ethoxide solution (32.5 mL, 21% w/v) was added over 1 h to asolution of hydrochloride (3.5 g, 0.05 mol) and phenolphthalein (5 mg)in ethanol (20 mL). After stirring for 3 hr at room temperature,acetonitrile (1.4 g) was added. The reaction was stirred for 2 h andthen heated at 40° C. for 48 h. The reaction mixture was cooled to roomtemperature and concentrated under vacuum. The residue was kept at roomtemperature for 48 h, purified on silica gel column eluting with 9:1dichloromethane:methanol to give N-Hydroxy-acetamidine (1.8 g, 73%). ¹HNMR (300 MHz, DMSO): 8.60 (s, 1H); 5.51 (bs, 2H); 1.60 (s, 3H).

Precursor 2Y

A solution of 4-fluoro-7-bromo-6-azaindole (100 mg, 0.46 mmol),N-Hydroxy-acetamidine (170 mg, 2.3 mmol),tetrakis(triphenylphosphine)palladium (200 mg, 0.17 mmol) andtriethylamine (0.2 mL, 1.4 mmol) in toluene (2.5 mL) was heated atreflux under an atmosphere of carbon monoxide for 18 h. The reactionmixture was cooled to room temperature and concentrated under vacuum.The residue was diluted with ethyl acetate (10 mL) and washed with water(2×25 mL). The organic layer was concentrated and purified onpreparative HPLC to give precursor 2y (5 mg, 5%). ¹H NMR (300 MHz,CDCl₃): 10.22 (bs, 1H); 8.32-8.31 (m, 1H); 7.55-7.53 (m, 1H); 6.81-6.79(m, 1H); 2.55 (s, 3H). LC/MS: (ES) m/z (M+H)⁺ =219. Rt=1.15 min.

Precursor 4R

Precursor 4r was prepared following the procedure previously describedfor compound 4k LC/MS: (ES) m/z (M+H)⁺ =291. Rt=0.87 min.

Example 300

The title compound was prepared following the general coupling proceduredescribed before for precursor 5a and using precursor 4k and benzoylpiperazine as the inputs. ¹H NMR (300 MHz, CDCl₃): 10.92 (bs, 1H);8.51-8.50 (m, 1H); 8.41-8.40 (m, 1H); 7.43 (m, 5H); 3.97-3.50 (m, 8H);2.58 (s, 3H). LC/MS: (ES⁺) m/z (m+H)⁺ =463. Rt=1.24 min.

Precursor 2Z

1-Methyl-1,2,4-triazole (249 mg, 3 mmol) was dissolved in anhydrous THF(3 mL) and cooled to −78° C. n-BuLi (2.5 M in hexane, 1.2 ml) was addedvia a syringe. After stirring for 10 min, ZnCl₂ (0.5 M in hexane, 6 mL)was added. The reaction mixture was stirred at −78° C. for 20 min, thenwarmed to room temperature. The resulting mixture was transferred via asyringe into a pressure flask which contained a mixture of4-fluoro-7-bromo-6-azaindole (215 mg, 1.0 mmol),tetrakis(triphenylphosphine)palladium (127 mg, 0.11 mmol) and dioxane (6mL). The reaction mixture was heated at 120° C. in the sealed flask for15 h, and then cooled to room temperature. Ethyl acetate (100 mL) wasadded to quench the reaction. The resulting mixture was washed withwater (2×20 mL). The organic layer was concentrated and purified onpreparative HPLC. Final crystallization in methanol/water gave Precursor2z (80 mg, 37%). ¹H NMR (300 MHz, CDCl₃): 11.10 (bs, 1H); 8.18-8.17 (m,1H); 8.02-8.01 (m, 1H); 7.50-7.48 (m, 1H); 6.74-6.72 (m, 1H); 4.52 (s,3H). LC/MS: (ES⁺) m/z (M+H)⁺ =218. Rt=1.23 min.

Precursor 4S

Precursor 4s was prepared following the procedure described before forprecursor 4m. LC/MS: (ES⁺) m/z (M+H)⁺ =293. Rt=0.92 min.

Example 301

The title compound was prepared following the example coupling proceduredescribed before for precursor 5a and using precursor 4s and (benzoylpiperazine as inputs. ¹H NMR (300 MHz, CDCl₃): 11.86 (bs, 1H); 8.37-8.36(m, 1H); 8.32-8.31 (m, 1H); 8.02-8.01 (m, 1H); 7.42 (m, 5H); 4.51 (s,3H); 3.95-3.51 (m, 8H). LC/MS: (ES⁺) m/z (M+H)⁺ =462 Rt=1.32 min.

Preparation of Precursor 4T

To a solution of 1-ethyl-3-methyl imidazolium chloride (2.7 g, 18 6mmol) and aluminum chloride (7.5 g, 55.8 mmol) was added precursor 2i(2.0 g, 9 3 mmol) followed by slow addition of ethyloxalylacetate (2.1ml, 18.6 mmol) at room temperature. The reaction was then stirred atroom temperature for 20 h, and quenched by slow addition of ice water(20 mL). A light brown solid precipitated out and was collected byfiltration and dried in air to provide compound precursor 4t (2.2 g,82%). LC/MS: (ES⁺) m/z (M+H)⁺ =289. Rt=0.85 min.

Preparation of Precursor 5AB

A mixture of compound precursor 4t (500 mg, 1.74 mmol), benzylpiperazinehydrochloride (395 mg, 1.74 mmol), DEBPT (520 mg, 1.74 mg) anddiisopropylethylamine (0.61 ml, 3.48 mmol) in 3 ml of DMF was stirred atrt for 20 h. The reaction mixture was diluted with EtOAc (50 ml) andwashed with water (50 ml). The aqueous layer was extracted with EtOAc(3×50 ml). The organic extracts were combined and dried over Mg₂SO₄,filtered and concentrated to dryness. The residue was redissolved inEtOAc and precursor 5ab crystallized out as a pale brownish solid andwas collected by filtration (221 mg, 27%). ¹H NMR (d, MeOD): 8.4 (s,1H), 8.1 (s, 1H), 7.5 (bs, 5H), 3.82-3.53 (m, 8H); MS m/z 461 (MH);Rt=1.24 min.

General Procedure for Preparing Examples 302-315

General Procedure for the Preparation of 7-N-Linked Heterocycles

A mixture of precursor 5ab for examples 302-313 or 5ac for Examples314-315, 15-30 equivalents of the corresponding amine, preferably 30equivalents were used, 1 equivalent of copper powder and 1 equivalent ofpotassium carbonate was heated at 160° C. for 4-7 hr in a sealed tube.The reaction was cooled to room temperature, diluted with EtOAc andfiltered through filter paper. The solvent was removed in vacuo and theresidue was diluted with methanol and purified by preparative HPLC.

Example 303

Example 303 was prepared from precursor 5ab and 1,2,4-triazole followingthe procedure described above. ¹H NMR (500 MHz, CDCl₃): 11.15 (bs, 1H);9.28 (s, 1H); 8.33-8.34 (m, 1H); 8.22 (s, 1H); 8.10 (s, 1H); 7.46-7.42(m, 5H); 3.90-3.48 (m, 8H). LC/MS: (ES⁺) m/z (M+H)⁺ =448. Rt=1.21 min.

Example 304

Example 304 was prepared from precursor 5ab and imidazole following theprocedure described above. ¹H NMR (500 MHz, CDCl₃): 13.35 (bs, 1H); 9.49(s, 1H); 8.35-8.30 (m, 1H); 8.20 (s, 1H); 7.97 (s, 1H); 7.56-7.53 (m,1H); 7.46-7.41 (m, 5H); 3.98-3.40 (m, 8H). LC/MS: (ES⁺) m/z (M+H)⁺ =447.Rt=1.25 min.

Example 305

Example 305 was prepared from precursor 5ab and pyrazole following theprocedure described above. ¹H NMR (500 MHz, CDCl₃): 11.52 (bs, 1H);8.65-8.64 (m, 1H); 8.27-8.26 (m, 1H); 8.05-8.04 (m, 1H); 7.81-7.80 (m,1H); 7.50-7.35 (m, 5H); 6.54-6.53 (m, 1H); 4.01-3.47 (m, 8H). LC/MS:(ES⁺) m/z (M+H)⁺ =447. Rt=1.25 min. Compound of example 222 was preparedfrom precursor 5i and morpholine following the procedure describedabove. ¹H NMR (300 MHz, CD₃OD₃): 8.38 (s, 1H); 7.86-7.84 (m, 1H);4.14-3.25 (m, 16H). LC/MS: (ES⁺) m/z (M+H)⁺ =466. Rt=0.988 min.

EXAMPLES 306 and 307

Examples 306 and 307 were prepared from precursor 5ab using the generalprocedure previously described above using 3-methyltriazole. Example306: ¹H NMR (500 MHz, CDCl₃): 9.14 (s, 1H); 8.32 (s, 1H); 8.06 (s, 1H);7.42 (m, 5H); 3.75-3.85 (m, 4H); 3.55-3.70 (m, 4H); 2.57 (s, 3H). LC/MS:(ES⁺) m/z (M+H)⁺ =462; rt=1.27 min. Example 307: ¹H NMR (500 MHz,CDCl₃): 8.29 (s, 1H); 8.17 (s, 1H); 8.05 (s, 1H); 7.42 (m, 5H);4.75-4.85 (m, 4H); 4.55-5.70 (m, 4H); 3.02 (s, 3H). LC/MS: (ES⁺) m/z(M+H)⁺ =462; rt=1.27 min.

Example 308

Example 308 was prepared from precursor 5ab and pyrrole following theprocedure described above. ¹H NMR (300 MHz, CD₃OD₃): 8.33-8.29 (m, 2H);7.49-7.40 (m, 5H); 7.38-7.37 (m, 2H); 6.42-6.41 (m, 2H); 3.91-3.40 (m,8H). LC/MS: (ES⁺) m/z (M+H)⁺=446. Rt=1.34 min.

Example 309

The title compound was prepared from precursor 5ab using the generalprocedure previously described using 3-aminopyrazole. ¹H NMR (300 MHz,DMSO):12.42 (bs, 1H); 8.34-8.33 (m, 1H); 8.31-8.30 (m, 1H); 8.04-8.03(m, 1H); 7.44 (bs, 5H); 5.93-5.92 (m, 1H); 3.80-3.16 (m, 8H). LC/MS:(ES⁺) m/z (M+H)⁺ =462. Rt=1.26 min.

Example 310

The title compound was prepared from precursor 5ab according to thegeneral procedure previously described using 3-methylpyrazole. ¹H NMR(500 MHz, CDCl₃): 11.59 (bs, 1H); 8.53-8.52 (m, 1H); 8.27-8.26 (m, 1H);8.02-8.01 (m, 1H); 7.46-7.42 (m, 5H); 6.32-6.31 (m, 1H); 3.82-3.48 (m,8H); 2.43 (s, 3H). LC/MS: (ES⁺) m/z (M+H)⁺ =461. Rt=1.50 min.

Example 311

The title compound was prepared from precursor 5ab according to thegeneral procedures previously described. ¹H NMR (500 MHz, CDCl₃): 11.92(bs, 1H); 8.28-8.27 (m, 1H); 8.08-8.07 (m, 1H); 7.47-7.42 (m, 5H);6.73-6.72 (m, 1H); 4.45-4.38 (m, 2H); 4.0-3.49 (m, 8H); 2.84 (s, 3H);1.44-1.37 (m, 3H). LC/MS: (ES⁺) m/z (m+H)⁺ =533. Rt=1.67 min.

Example 312

Example 312 was prepared from precursor 5ab according to the generalprocedure previously described using 3-methylpyrazole. ¹H NMR (300 MHz,CDCl₃): 11.61 (bs, 1H); 8.23-8.22 (m, 1H); 8.06-8.05 (m, 1H); 7.67-7.66(m, 1H); 7.42 (m, 5H); 6.25 (m, 1H); 3.89-3.48 (m, 8H); 2.82 (s, 3H).LC/MS: (ES⁺) m/z (M+H)⁺ =461. Rt=1.41 min.

Example 313

Example 313 was prepared from precursor 5ab according to the generalprocedure previously described using 3-amino-1,2,4-triazole. ¹H NMR (500MHz, CDCl₃): 11.12 (bs, 1H); 8.89-8.88 (m, 1H); 8.29-8.28 (m, 1H);8.03-8.02 (m, 1H); 7.58-7.51 (m, 5H), 3.87-3.50 (m, 8H). LC/MS: (ES⁺)m/z (M+H)⁺ =463. Rt=1.16 min.

Precursor 5AC

Precursor 5ac was prepared from precursor 4t following the proceduredescribed for precursor 5ab using 1-benzoyl-3-(R)-methylpiperazineinstead of benzylpiperazine. LC/MS: (ES⁺) m/z (M+H)⁺ =474-475. Rt=1.20min.

Example 314

Example 314 was prepared from Precursor 5ac following the generalprocedure described above for 7-N-linked heterocycles. ¹H NMR (500 MHz,CDCl₃): 8.75 (s, 1H); 8.36 (m, 1H); 8.08 (m, 1H); 7.45-7.38 (m, 5H);4.75-2.947 (series of multiplets, 7H); 1.37-1.30 (m, 3H).

Example 315

Example 315 was prepared from Precursor 5ac following the generalprocedure described above for 7-N-linked heterocycles. ¹H NMR (500 MHz,CDCl₃): 9.15 (s, 1H); 8.32 (d, J=3.0 Hz, 1H); 8.16 (m, 1H); 7.92 (s,1H); 7.45-7.38 (m, 5H); 4.72-2.94 (series of multiplets, 7H); 2.57 (s,3H); 1.37-1.30 (m, 3H); LC/MS: (ES⁺) m/z (M+H)⁺ =476. Rt=1.29 min.

Synthetic Experimental Procedures for Best Preparation of Example 216(Scheme 80)

5-Amino 2 methoxypyridine (50 g, 0.4 mol) was added to a stirringmixture of absolute ethanol (280 ml) and HBF₄ (48% in water, 172 ml) andcooled to 0° C. Sodium nitrite (129 g) was dissolved in water (52 ml)and added portion-wise over 1 h). The stirring was continued at 0° C.for 2 hr. The reaction mixture was diluted with ether (1 L). The solidproduct was collected by filtration and washed with 500 ml of 50:50EtOH/ether and subsequently several times with ether until the productwas slightly pinkish in color. The pale pink solid 90 g (˜100% yield)was kept in a dessicator over P₂O₅.

The same procedure was followed to perform the reaction on larger scale:

(1) (200 g, 1.6 mol); HBF₄ (688 ml); NaNO₂ (116 g); EtOH (1.12 L); H₂O(208 ml)

The reaction was run 4 times (total 800 grams (1-80)). The product wasdried over P₂O₅ for 48 hr. (only 24 hr for first batch).

A total of 1,293 g of (2-80) was obtained, (91% yield).

Ref: J. Heterocyclic Chem., 10, 779, 1973 (for above reactions,including analytical data)

The decomposition of the diazonium salt was run in 3 batches of:

206 g, 219 g and 231 g using 1.3 L, 1.4 L and 1.6 L of anhydrous toluenerespectively.

The toluene was preheated under nitrogen to 100° C. (internaltemperature) in a 2L 3-neck round bottom flask provided with amechanical stirrer. The solid was added solid portion-wise via a scoopthrough a powder funnel which was attached to an adapter with slightoutward positive nitrogen flow. During addition, the temperature wasmaintained between 99-102° C. (set at 100° C.) and stirred vigorously.Total addition time was 60 min. for the smaller two batches and 70 min.for the last one. After the addition was finished, each stirringreaction was heated at 110° C. for 1 hr. The heating mantle was removedand stirring was stopped. The reactions were allowed to stand for 2 hr(ambient temp achieved). Safety Note: The reaction contains BF3 soworking with the reaction hot exposes vapors which caused skinirritation with some people. No incidents were noted at ambienttemperature (6 different people). The hot toluene from the reaction waspoured into a 4 L Erlenmeyer (a dark brown oil and residue remained inthe flask). The residue was washed with 50 ml of toluene and poured intothe original toluene extracts.

Add 1.5 L of 1N NaOH to toluene layer, extract and wash with ˜100 ml ofsat aq. NaCl.

Combine NaCl with NaOH layer, re-extract with 150 ml of toluene, washwith 50 ml of sat NaCl.

Combine toluene layers.

Add 1 L of 1N NaOH to residue in reaction flask and swirl to dissolve asmuch residue as possible then add 500 ml Et2O and pour into Erlenmeyer.

Add ˜500 ml more of 1 N NaOH to reaction flask and swirl ˜500 ml ofEt2O.

Combine dark Et2O and NaOH washings in erlenmyer flask.

Et2O/NaOH mixture was poured through powder funnel containing plug ofglass wool to collect dark viscous solid. (Add ˜500 ml more ether towash) into 6 L sep funnel

Extract. Wash ether layer with ˜200 ml of H₂O and then 100 ml of satNaCl.

Combine all washings with original NaOH aq. Layer and re-extract with500 ml of ether. Wash with 100 ml H₂O and 100 ml of NaCl.

Combine ether extracts. Toluene and ether extracts were checked by LC/MSclean product.

The ether was concentrated on a rotovap and the residue was combinedwith the toluene extracts to make a homogeneous solution which is takento next step as is.

The other two rxns were combined and worked up in the same way.

All aqueous layers were checked by LC/MS=no product.

Ref: J. Heterocyclic Chem., 10, 779, 1973 (for above reactions,including analytical data)

A total of 4.6 L of toluene solution containing 3-80 was placed inseveral sealed tubes and treated with 900 ml of 35% HCl at 145° C. for 2hr. LC/MS showed no starting material, only 4. The toluene solution wasdecanted and discarded. The aqueous phase was washed with EtOAc andconcentrated down to remove volatiles to afford a brown solid containingthe desired fluoro-hydroxypyridine 4-80.

A total of 244 g of this solid was collected and taken to next step asis (it was not completely dry).

Note: We have subsequently run this by decanting the toluene layer firstprior to heating to reduce volumes. Same reaction was carried out usingHBr (48% in H₂O) at 100° C. for 6 h with similar result to theliterature procedure 49% yield.

Ref: J. Heterocyclic Chem., 10, 779, 1973 (for above reactions,including analytical data)

The solid from above containing (4-80) was divided in 4 batches andtreated with H₂SO₄ and fuming HNO₃ as shown below. The amounts usedwere:

batch 1 batch 2 batch 3 batch 4 (1) 25 g 54 g 75 g 90 g fuming HNO₃ 20.8ml 45 ml 62.4 ml 75 ml H₂SO_(4·(for addition)) 5.6 ml+ 12 ml+ 16.8 ml+20 ml+ (for soln) 56 ml 120 ml 168 ml 200 ml

Compound 4-80 was dissolved in sulfuric acid (the larger amountsindicated above) at rt and then heated to 65° C. A preformed solution offuming nitric acid and sulfuric acid (the smaller amount indicatedabove) was added dropwise. The temperature was kept between 65° C. and80° C. (rxn is exothermic and although the bath is at 65° C.,temperature goes higher, usually 75, sometimes 80° C.). After theaddition was complete, the reaction mixture was heated at 65° C. for anadditional hr. The reaction mixture was then cooled to rt and poured ina flask containing ice) (20 g of ice/gr compound, evolution of gasoccurred). A solid precipitated out and it was collected by filtration(¹HNM” showed 4-80 and something else (discarded)).

The aqueous layer was extracted with AcOEt several times (3-5) andconcentrated on a rotary evaporator under vacuum to afford a solid thatwas triturated with ether to afford 5-80 as a bright yellow solid. Atotal of 117 g of desired product was collected in the first crop (27%yield from diazonium salt). A portion did not crystallize: this oil wastriturated with MeOH and Et₂O to afford 3.6 g of 5-80; anotherprecipitation from the mother liquid afforded an additional 6.23 g ofthe desired product 5-80

Total: 117.0+3.6+6.23=126.83. 30.4%). Yield for 3 steps (decompositionof diazonium salt; deprotection and nitration).

Analytical data from Notebook: 53877-115: ¹H NMR (δ, MeOD): 8.56-8.27(dd, J=7.5, 3.3 Hz, 1H), 8.01 (d, J=3.3 Hz, 1H); LC/MS (M+1)⁺ =158.9;rt=0.15 min.

Note: A portion of the aqueous acidic solution was taken and neutralizedwith Na₂CO₃ until effervescence stopped and then it was extracted withAcOEt

A different product was obtained. No desired product in these extracts.

A total of 117 g of 5-80 was divided in 4 batches of 30 g×3 and 27 g×1and treated with POBr₃ (3 equiv.; 163 g×3 and 155 g×1) and a catalyticamount of DMF (15 ml) at rt (DMF was added carefully

gas evolution). After 5 min. at room temperature, the solutions wereheated at 110° C. for 3 hr. LC/MS showed starting material had beenconsumed. The reaction mixtures were allowed to cool to rt. The reactionflasks were placed in an ice bath; and then ice was added very slowlyand carefully portionwise into the flask, gas evolution was due to HBrformation; the liquid and black solid that formed was poured into abeaker with ice. EtOAc was added and the mixture was then extractedseveral times with EtOAc. The organic layer was washed with saturatedaq. NaHCO₃; H₂O and brine; dried over Na₂SO₄ and filtered. The productwas dried in the pump overnight to provide 123 g of 6-80 as a brownsolid (77% yield).

Note: Reaction is completed within 1 h.

¹H NMR (δ, CDCl₃):8.52 (m, 1H), 7.93 (m, 1H).

800 ml of vinyl magnesium bromide (1M in THF, Aldrich) was cooled below−60° C. with vigorous stirring under N₂. 2-bromo-5-fluoro-3-nitropyridine (43.3 g, 0.196 mol) in 200 ml THF was added dropwise viaaddition funnel at such a rate that the temp was kept below −60° C. Thistook ˜1.25 hr. The reaction mixture was warmed to −40 to −50° C. andstirred for 1 hr more. Then 1L of saturated aqueous NH₄Cl was addedslowly and cautiously. At first, foaming occurred and considerable solidwas present, but this essentially dissolved as the addition wascompleted and the material warmed to rt. The layers were separated andthe aqueous layer extracted 3 times with ethyl acetate. The organicextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated to afford ˜50 g of a black gummy solid. HPLC indicated57-58% product. To this was added CH₂Cl₂ and the solid was collected byfiltration and washed with CH₂Cl₂ to afford 12.5 g of product as a brownsolid. The reaction was repeated on exactly the same scale and worked upin the same manner. From CH₂Cl₂ trituration there was obtained 12.4 g ofPrecursor 2i (HPLC ˜97% pure). The crude was recovered and allowed tostand in dichloromethane. Upon standing 3.6 g of additional productseparated and was recovered by filtration.

Total yield=29.5 g (35%).

¹H NMR (δ, CDCl₃): 8.69 (bs, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.41 (m, 1H),6.77 (m, 1H); LC/MS (M+1)⁺ =216.-217.9; rt=1.43 min.

Reaction was carried in a 250 ml flask (foaming occurred upon heatingand the big size flask is more convenient). A mixture of precursor 2i (3g, 13.95 mmol), 1,2,3-triazole (15 g, 217.6 mmol, 15 eq), K₂CO₃ (1.9 g,13.95 mmol, 1 eq) and Cu(0)(0.9 g, 13.9 mmol, 1 eq) was heated at 160°C. for 7 hr (from rt to 160° C. total 7 hr) under N₂ (depending on theCu(0) lot, reaction time may vary from 2 hr to 7 hr). The resultingmixture was diluted with MeOH, filtered through filter paper (to removethe copper). Washed with MeOH (20 ml) and water (30 ml).

The filtrate was concentrated (remove solvent in rotovap) and dilutedwith ethylacetate. The aqueous layer was extracted with ethylacetate.The combined organic layer was dried over sodium sulfate, filtered andconcentrated. The residue was dissolved in MeOH (20 ml), 7-80 (750 mg)crystallized from the methanol as a white solid and was collected byfiltration. (Slow gradient volume, silica gel hex/AcOEt (0→18%) of themother liquids usually affords 5-10% more of 7-80.

¹H NMR (6, CDCl₃): 10.47 (bs, 1H), 8.76 (s, 1H), 7.94 (s, 1H), 7.89 (s,1H), 7.53 (m, 1H), 6.78 (m, 1H); LCMS (M+1)⁺ =204; rt=1.29 min.

Ethyl methylimidazolium chloride (4.3 g, 29.6 mmol, 3 eq) was placed ina 250 ml flask. AlCl₃ (11.8 g, 88.6 mmol, 9 eq) was added into the flaskin one portion. A liquid suspension was formed (some of AlCl₃ remainedas solid). After stirring for 5-10 min. compound (1) (2.0 g, 9.85 mmol)was added in one portion followed by slow addition (via a syringe) ofethyl chlorooxalacetate (3.3 ml, 29.6 mmol, 3 eq). The reaction wasstirred at room temperature for 20 hr. LCMS indicated compound 8-80:compound 7-80=6:2. (Compound I has strong UV absorption) The reactionwas quenched by carefully adding ice water (˜75 ml) at 0° C. A yellowsolid precipitated at this point. The resulting suspension was filteredand the solid was washed with water. MeOH and ethyl acetate (to removeunreacted SM) and the solid was dried in air. (LCMS purity 70%˜80%) 2 gof solid containing 8-80 was obtained and taken to the next step withoutfurther purification. LCMS (M+1)⁺ =276; rt=0.97 min.

A mixture of compound 8-80 (4.9 g, 17 8 mmol) & N-benzoylpiperazinehydrochloride 8a-80 (HCl salt; 6.0 g, 26.7 mmol, 1.5 eq) in DMF (30 ml)was stirred at RT overnight (16 hr). A slurry was formed. An additional20 ml of DMF was added into the slurry. Then HATU (12.2 g, 26.7 mmol,1.5 eq) was added followed by DMAP (4.3 g, 35.6 mmol, 2 eq). Thereaction mixture was stirred for 30 min. LCMS indicated the startingmaterial 8-80 was completely converted to product (EXAMPLE 216). Theresulting mixture was filtered and the solid washed with water. Thefiltrate was concentrated in vacuo. Water was added to the residue andthe solid was collected by filtration. The solids were combined andwashed with water, MeOH and EtOAc. Then the solid was dried in air. LCMS& HPLC showed BMS-585248, >99% pure. The solid product was furtherpurified by precipitation and crystallization in 5-10% CH₃OH/CHCl₃.

Purification of Example 216

Crude compound of Example 216 obtained as above (15.3 g) was dissolvedin 10% MeOH/CHCl₃ (600 ml). A light brown suspension was formed,filtered through filter paper and washed with MeOH a twice. The brownishsolid was discarded (˜1.2 g). Example 216 was crystallized in thefiltrate, the solid was collected by filtration and the white solid wasdried in air. The filtrate was used to repeat the crystallizationseveral times. The solid obtained from each filtration was analyzed byHPLC. All the pure fractions were combined. The not so pure fractionswere resubjected to crystallization with MeOH & CHCl₃. A total of 12.7 gof Example 216 was obtained from recrystallization and precipitation.The mother liquid was concentrated and purified on silica gel column(EtOAc, then CHCl₃/MeOH (0-2%)) to provide 506 mg of product) as a whitesolid. ¹H NMR (d, DMSO) 13.1 (bs, 1H), 9.0 (s, 1H), 8.4 (s, 1H), 8.3 (s,1H), 8.2 (s, 1H), 7.4 (bs, 5H), 3.7 (bs, 4H), 3.5 (bs, 4H); MS m/z 448(MH). Anal: Calc for C₂₂H_(B)FN₇O₃; C, 59.05; H, 4.05; N, 21.91; F,4.24. Found; C, 57.28; H, 4.14; N, 21.22; F, 4.07%.

Scheme 81 is a preferred method for making compounds of Formula I and Iawhere R² is methoxy. This is specifically exemplified for thepreparation of compound Example 316 and 317.

Preparation of 3-methyl-1,2,4-triazole (2-81)

Procedure:

A solid mixture of formic hydrazide (68 g, 1.13 mol) and thioacetamide(85 g, 1.13 mol) in a 500 mL-RBF was heated with stirring at 150° C.(oil bath temp.) for 1.5 hrs with a gentle stream of nitrogen, removingH₂S and water (about 18 mL of liquid collected) formed during thereaction. The reaction mixture was distilled under reduced pressure,collecting 60.3 g (0.726 mol, Y. 63.3%) of the title compound at 102°C./0.35-1 mmHg as white solid after removing a liquid forerun.: ¹H NMR(CDCl₃) δ ppm 2.51 (3H, s, 3-Me), 8.03 (1H, s, 5-H), 9.5 (1H, br, NH);TLC Rf (10% MeOH/CH₂Cl₂)=0.3 (phosphomolybdate-charring, white spot).

Reference: Vanek, T.; Velkova, V.; Gut, Jiri Coll. Czech. Chem. Comm.1985, 49, 2492.

Preparation of 3-81

Procedure:

A 500 mL round bottom flask was loaded with4-methoxy-7-chloro-6-azaindole precursor 2e (9.1 g, 50 mmol; dried invacuo), potassium carbonate (13.8 g, 100 mmol, 2 eq.), copper powder(6.35 g, 100 mmol, 2 eq.), and 3-methyl-1,2,4-triazole (83 g, 1.0 mol,20 eq.). The solid mixture was heated to melt at 170-175° C. (externaloil bath temperature) under gentle stream of anhydrous nitrogen for 12h, by which time HPLC analysis indicates the amount of the peak for thestarting material becomes 5-30% and the desired product peak becomesabout 45% with isomeric by-product peak becomes 15%. As the reactionmixture cools, MeOH (150 mL) was added slowly to the stirred warmmixture. Upon cooling, the insoluble material (copper powder) wasfiltered through a Celite pad, and rinsed with methanol. The filtratewas concentrated in vacuo to a thick paste which was diluted with water(1 L) and extracted with EtOAc (3×150 mL). The EtOAc extracts were dried(MgSO₄), filtered and concentrated to obtain about 8 g of crude residuewhich was crystallized by dissolving in hot CH₃CN (50 mL), followed bydiluting with water (100 mL) and cooling at 0° C. to collect 1.45 g(12.7%) of the title compound as white solid. The filtrate was purifiedby C-18 reverse phase silica gel (YMC ODS-A 75 μm) eluted with 15-30%CH₃CN/H₂O. Appropriate fractions were combined and the aqueous solutionafter removing CH₃CN by rotary evaporator was lyophilized to giveadditional 1.15 g of the title compound 3-81. The crude aqueous layerwas further extracted with EtOAc several times. The ethyl acetateextracts were dried (MgSO4), filtered, concentrated, and crystallizedfrom MeOH to give additional 200 mg of the title compound 3-81. Thetotal yield: 2.8 g (12.2 mmol, Y. 24.5%); MS m/z 230 (MH), HRMS (ESI)m/z calcd for C₁₁H₁₂N₅O (M+H), 230.1042. found 230.1038 (A -1.7 ppm); ¹HNMR (CDCl₃) δ ppm 2.54 (3H, s, CH₃), 4.05 (3H, s, OCH₃), 6.73 (1H, s,H-3), 7.40 (1H, s, H-2), 7.56 (1H, s, H-5), 9.15 (1H, s, triazole-H-5);¹³C NMR (CDCl₃, 125.7 MHz) δ ppm 14.2 (triazole-Me), 56.3 (OMe), 100.5(C-3), 116.9 (C-5), 123.5, 127.2, 127.5 (C-2), 129.5 (C-7), 141.2(C-5′), 149.5 (C-4), 161.8 (C-3′); Anal. Calcd for C₁₁H₁₁N₅O: C, 57.63;H, 4.83; N, 30.55. found C, 57.37; H, 4.64; N, 30.68.

The structure was confirmed by a single X-ray crystallographic analysisusing crystals obtained from C-18 column fractions. A portion of C-18column fractions containing a mixture of the desired3-methyl-1,2,4-triazolyl analog 3-81 and isomeric5-methyl-1,2,4-triazolyl analog 4-81 was further purified by C-18reverse phase column eluting with 8-10% CH₃CN/H₂O. Appropriate fractionswere extracted with CH₂Cl₂, and slow evaporation of the solvent gavecrystalline material of the isomeric7-(5-methyl-1,2,4-triazolyl)-4-methoxy-6-azaindole (4-81): MS m/z 230(MH), ¹H NMR (CDCl₃) δ ppm 3.05 (3H, s, CH₃), 4.07 (3H, s, OCH₃), 6.74(1H, q, J=2.4, H-2), 7.37 (1H, t, J=2.4, H-3), 7.65 (1H, s, H-5), 8.07(1H, s, triazole-H-3). The structure was confirmed by a single X-raycrystallographic analysis.

Preparation of 5-81

Procedure:

AlCl₃ (40 g, 0.3 mol, 15 eq.) was dissolved in a solution of CH₂Cl₂ (100mL) and nitromethane (20 mL) under dry nitrogen. To this solution wasadded compound 3-81 (4.58 g, 0.02 mol) under stirring and under N₂,followed by methyl chlorooxoacetate (9.8 g, 0.08 mol, 4 eq.). Themixture was stirred under N₂ at room temperature for 1.5 h. The mixturewas added drop-wise to a cold and stirred solution of 20% aqueousammonium acetate solution (750 mL). The mixture was stirred for 20 minand the resultant precipitate was filtered, washed thoroughly with waterand dried in vacuo to obtain 4.7 g (0.015 mol, Y. 75%) of the titlecompound 5-81 as white solid: MS m/z 316 (MH); HRMS (ESI) m/z calcd forC₁₄H₁₄N₅O₄ (M+H), 316.1046. found 316.1041 (Δ-1.6 ppm); ¹H NMR (CDCl₃,500 MHz) δ ppm 2.58 (3H, s, CH₃), 3.96 (3H, s, OCH₃), 4.05 (3H, s,OCH₃), 7.76 (1H, s, H-5), 8.34 (1H, d, J=3 Hz, H-2), 9.15 (1H, s,triazole-H-5), 11.0 (1H, brs, NH). More title compound 5-81 andhydrolyzed acid 6-81 can be obtained from the filtrate by acid-baseextraction with EtOAc.

Preparation of 6-81

Procedure:

To a suspension of the methyl ester 5-81 (2.2 g, 7 0 mmol) in MeOH (50mL) was added 0.25M NaOH solution in water (56 mL, 14 mmol, 2 eq.) atroom temperature and the mixture stirred for 15 min by which time HPLCindicated the hydrolysis was complete. The mixture was concentrated invacuo quickly to remove MeOH, and to the residual solution was addedwater (100 mL) and 1N HCl (14 mL) with stirring to neutralize themixture. The resultant fine precipitate was filtered, washed with waterand dried in vacuo to obtain 1.98 g (6.58 mmol, Y. 94%) of the titlecompound 6-81 as off-white solid: MS m/z 302 (MH); ¹H NMR (DMSO-d₆, 500MHz) δ ppm 2.50 (3H, s, overlapped with DMSO peaks), 3.98 (3H, s, CH₃O),7.87 (1H, s, H-5), 8.29 (1H, d, J=3.5 Hz, H-2), 9.25 (1H, s,triazole-H-5), 12.37 (1H, s, NH).

Alternative procedure: To a suspension of the methyl ester 5-81 (10.7 g,34 mmol) in MeOH (150 mL) was added 0.25M NaOH solution in water (272mL, 68 mmol, 2 eq.) at room temperature and the mixture stirred for 20min by which time HPLC indicated the hydrolysis was complete. Themixture was concentrated in vacuo quickly to remove MeOH, and theresidual solution was extracted with EtOAc to remove any neutralimpurities. To the aqueous phase was added 1N HCl (68 mL, 68 mmol) toneutralize the product. The resultant mixture was frozen and lyophilizedto obtain 14.1 g (33 7 mmol, Y. 99.2%) of the title compound 6-81,containing 2 mole equivalents of NaCl as off-white solid. This materialwas used in the subsequent reaction without further purification. Thesodium salt of the title compound 6-81 was obtained by C-18 reversephase column chromatography after sodium bicarbonate treatment:HPLC >97% (AP, uv at 254 nm); HRMS (Na salt, ESI−) m/z calcd forC₁₃H₁₀N₅O₄ (M−H), 300.0733. found 300.0724 (Δ−3 ppm); ¹H NMR (Na salt,DMSO-d₆, 500 MHz) δ ppm 2.37 (3H, s, Me), 3.83 (3H, s, CH₃O), 7.56 (1H,s, H-5), 8.03 (1H, s, H-2), 9.32 (1H, s, triazole-H-5); ¹³C NMR (Nasalt, DMSO-d₆, 125.7 MHz) δ ppm 13.8 (triazole-Me), 57.2 (OMe), 114.8(C-3), 120.0 (C-5), 125.1, 143.5 (C-5′), 149.8 (C-4), 160.0 (C-3′),171.7, 191.3.

Preparation of Example 316

Procedure:

To a solution of the acid 6-81 (3.01 g, 10 mmol) and benzoylpiperazinehydrochloride (3.39 g, 15 mmol) in DMF (50 mL) was added triethylamine(10.1 g, 100 mmol, 10 eq.), followed by1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC; 5.75g, 30 mmol) under N₂ and the mixture stirred at room temperature for 22h after sonication and at 40° C. for 2 h. The mixture was concentratedin vacuo to remove DMF and TEA, and to the residual solution was addedwater (200 mL) under stirring and sonication. The precipitates formedwere collected, washed with water and dried in vacuo to obtain 2.8 g(5.9 mmol, Y. 59%) of the title compound Example 316 as off-white solid.The filtrate was extracted with CH₂Cl₂ (×2). The CH₂Cl₂ extracts weredried (Na₂SO₄), filtered and concentrated to gum which was trituratedwith Et₂O to obtain a solid. This solid was suspended and trituratedwith MeOH to obtain 400 mg of the title compound Example 316 asoff-white solid. Total yield: 3.2 g (6.8 mmol, Y. 68%): MS m/z 474 (MH);HRMS (ESI) m/z calcd for C₂₄H₂₄N₇O₄ (M+H) 474.1890. found 474.1884 (A-1.2 ppm); ¹H NMR (DMSO-d6) δ ppm 2.50 (3H, s, overlapped with DMSOpeaks), 3.43 (4H, br, CH₂N), 3.68 (4H, br, CH₂N), 3.99 (3H, s, CH₃O),7.46 (5H, br. s, Ar-Hs), 7.88 (1H, s, indole-H-5), 8.25 (1H, s,indole-H-2), 9.25 (1H, s, triazole-H-5), 12.40 (1H, s, NH); ¹³C-NMR(DMSO-d6) δ ppm 13.78, 40.58, 45.11, 56.78, 114.11, 120.95, 122.71,123.60, 126.98, 128.34, 129.6, 135.43, 138.52, 142.10, 149.15, 161.29,166.17, 169.22, 185.42; UV (MeOH) λmax 233.6 nm (e 3.43×10⁴), 314.9 nm(e 1.73×10⁴); Anal: Calc for C₂₄H₂₄N₇O₄ 0.1/5H₂O; C, 60.42; H, 4.94; N,20.55. Found; C, 60.42; H, 5.03; N, 20.65; KF (H₂O) 0.75%.

This reaction can also be performed by use of HATU and DMAP to providemore consistent yield of the title compound: To a suspension of the acid6-81 (15 6 mmol) and HATU[O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphonate] (8.90 g, 23.4 mmol; 1.5 eq.) in DMF (60 mL) and CH₂Cl₂ (60 mL)was added a mixture of DMAP (5.72 g, 46.8 mmol, 3 eq.) andbenzoylpiperazine hydrochloride (5.30 g, 23.4 mmol; 1.5 eq.) in DMF (60mL) at room temperature and the mixture was stirred under nitrogenatmosphere for 4 hrs. The mixture was concentrated in vacuo to removeCH₂Cl₂ and most of DMF, and to the residual solution was added waterunder stirring and sonication. The precipitates formed were collected,washed with water and dried in vacuo to obtain 5.38 g (11.4 mmol, Y.72.8%) of the title compound Example 316 as off-white solid: HPLC >95%(AP, uv at 254 nm).

Preparation of Example 317

Procedure:

To a solution of the acid 6-81, containing 2 mole equivalent of NaCl(4.1 g, 9 8 mmol) in CH₂Cl₂ (30 mL) and DMF (30 mL) was added at −10° C.under anhydrous nitrogen HATU[0-(7-azabenzotriazol-lyl)-N,N,N′,N′-tetrmethyluroniumhexafluorophosphate] (5.59 g, 14.7 mmol; 1.5 eq.), and stirred at −10°C. for 30 min. To this mixture was added a solution of2-(R)-methyl-N-benzoylpiperazine trifluoroacetate (4.7 g, 14.7 mmol; 1.5eq.) and dimethylaminopyridine (3.5 g, 29 mmol; 3 eq.) in DMF (30 mL)and CH₂Cl₂ (30 mL) and the mixture stirred at room temperatureovernight, by which time HPLC analysis indicated reaction wasessentially complete. The mixture was concentrated in vacuo to removevalatiles and DMF, and to the residue was added water (˜150 mL) understirring and sonication. The precipitates formed were collected, washedwith water and dried in vacuo to obtain 4.3 g of the title compoundExample 317 as off-white solid. This was dissolved in 20% MeOH in CH₂Cl₂(about 250 mL), removing any insoluble material, and the filtrate wasconcentrated in vacuo to remove more volatile CH2Cl|2. The resultantprecipitate was collected, washed with MeOH and then with Et₂O to obtain3.5 g (7.18 mmol, Y. 73.2%; AP>99%) of the title compound Example 317 asoff-white solid: LC/MS m/z 488 (MH); ¹H NMR (DMSO-d6) δ ppm 1.15, 1.22(3H, 2d, J=7 Hz), 2.50 (3H, s, overlapped with DMSO peaks), 3-4.3 (8H,m, CH₂N), 3.98, 4.00 (3H, s, CH₃O), 7.45 (5H, m, Ar-Hs), 7.89 (1H, s,indole-H-5), 8.19, 8.26 (1H, 2s, indole-H-2), 9.24, 9.25 (1H, 2s,triazole-H-5), 12.40 (1H, br.s, NH); Anal: Calc for C₂₅H₂₅N₇O₄; C,61.59; H, 5.16; N, 20.11. Found; C, 61.69; H, 5.27; N, 20.10; KF(H₂O)<0.1%.

Notes:

The following compounds, Examples 187, 245, and 241, were also preparedby the method described above using appropriate azoles (1,2,4-triazolefor Example 187, and Example 245; 3-methylpyrazole for Example 241.

Preparation of Example 316 Alternate Preparation of Example 316

A mixture of compound precursor 5b (150 mg, 0.35 mmol),3-methyl-1,2,4-triazole (581 mg, 7 mmol; 20 eq.; prepared by the methoddescribed in Coll. Czech. Chem. Comm. 1985, 49, 2492), copper powder (45mg, 0.7 mmol; 2 eq.), potassium carbonate (97 mg, 0.7 mmol; 2 eq.) wasflushed with anhydrous nitrogen and heated in a sealed tube at 160° C.for 11 h. Upon cooling, to the mixture was added MeOH, and the insolublematerial was filtered. The filtrate was concentrated in vacuo andpurified by C-18 reverse phase column (Prep. System eluting withMeOH-water containing 0.1% TFA) to obtain 19 mg (0.040 mmol, Y. 11%) ofthe title compound Example 216 as amorphous powder (TFA salt): MS m/e474 (MH); ¹H NMR (DMSO-d6) δ ppm 2.50 (3H, s, overlapped with DMSOpeaks), 3.44 (4H, br, CH₂N), 3.68 (4H, br, CH₂N), 4.00 (3H, s, CH₃O),7.46 (5H, br. s, Ar-Hs), 7.89 (1H, s), 8.25 (1H, s), 9.24 (1H, s), 12.41(1H, s, NH).

Alternate Preparation of Example 317

A mixture of compound 5z (220 mg, 0 5 mmol), 3-methyl-1,2,4-triazole(830 mg, 10 mmol; 20 eq.; prepared by the method described in Coll.Czech. Chem. Comm. 1985, 49, 2492), copper powder (63.5 mg, 1 mmol; 2eq.), potassium carbonate (138 mg, 1 mmol; 2 eq.) was flushed withanhydrous nitrogen and heated in a sealed tube at 160° C. for 11 h. Uponcooling, to the mixture was added MeOH, and the insoluble material wasfiltered. The filtrate was concentrated in vacuo and purified by C-18reverse phase column (Prep. System eluting with gradient 0-70%MeOH-water containing 0.1% TFA) to obtain 24 mg (0.049 mmol, Y. 9.8%) ofthe title compound Example 317 as amorphous powder (TFA salt): MS m/e488 (MH); ¹H NMR (CD₃OD) δ ppm 1.30, 1.35 (3H, 2d, J=7 Hz), 2.54 (3H, s,CH₃), 3-4.5 (8H, m, CH₂N), 4.04, 4.05 (3H, 2s, CH₃O), 7.46, 7.47 (5H,2s, Ar-Hs), 7.85, 7.86 (1H, 2s), 8.28, 8.31 (1H, 2s), 9.22 (1H, s).

Preparation of Example 318

A mixture of compound 5b (150 mg, 0.35 mmol), 4-methylimidazole (517 mg,6 2 mmol; 18 eq.; Aldrich), copper powder (26 mg, 0.42 mmol; 1.2 eq.),potassium carbonate (57 mg, 0.42 mmol; 1.2 eq.) was flushed withanhydrous nitrogen and heated in a sealed tube at 160° C. for 6 h. Uponcooling, to the mixture was added MeOH, and the insoluble material wasfiltered. The filtrate was concentrated in vacuo and purified by C-18reverse phase column eluting with 15% CH₃CN-water containing 0.1% TFA toobtain 32 mg (0.068 mmol, Y. 19%) of the title compound Example 318 asamorphous powder (TFA salt). H-NMR indicates contamination of about 30%of the isomeric product, 5-methylimidazolyl analog: MS (ES) m/e 473(MH); ¹H NMR (CD₃OD) δ ppm 2.25 (s), 2.51 (3H, s, CH₃), 3.63 (4H, br,CH₂N), 3.9 (4H, br, CH₂N), 4.13 (3H, s, CH₃O), 4.15 (s), 7.50 (5H, br.s, Ar-Hs), 7.60 (s), 7.89 (1H, s), 8.03 (1H, s), 8.11 (s), 8.43 (1H, s),9.35 (s), 9.42 (1H, s).

Preparation of Example 319

A mixture of precursor 4-81b (30 mg, 0.11 mmol; prepared from7-(5-methyl-1,2,4-triazolyl)-4-methoxy-6-azaindole by the method usedfor the best mode-preparation of Example 316), benzoylpiperazinehydrochloride (39 mg, 0.17 mmol), triethylamine (200 mg, 1.9 mmol; 18eq.), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(EDC; 77 mg, 0.45 mmol) in 1:1 DMF-NMP (1 mL) was stirred under N₂ atroom temperature for 20 h. The mixture was concentrated in vacuo toremove DMF and to the residue was added water and the mixture stirred toform precipitates which were collected and dried to obtain 14 mg (0.030mmol, Y. 27%) of the title compound Example 319 as amorphous powder: MSm/e 474 (MH); ¹H NMR (DMSO-d6) δ ppm 2.67 (3H, s, CH₃), 3.44 (4H, br,CH₂N), 3.68 (4H, br, CH₂N), 4.02 (3H, s, CH₃O), 7.46 (5H, br. s, Ar-Hs),7.98 (1H, s), 8.21 (1H, s), 8.24 (1H, s), 12.57 (1H, s, NH).

Preparation of Example 320

A mixture of compound 4-81b (30 mg, 0.11 mmol; prepared from7-(5-methyl-1,2,4-triazolyl)-4-methoxy-6-azaindole by the method usedfor the best mode-preparation of Example 316),2R-methyl-1-benzoylpiperazine trifluoroacetate (54 mg, 0.17 mmol),triethylamine (200 mg, 1.9 mmol; 18 eq.),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC; 77mg, 0.45 mmol) in 1:1 DMF-NMP (1 mL) was stirred under N₂ at roomtemperature for 20 h. More EDC (20 mg) was added to the mixture andstirred for additional 6 h. The mixture was concentrated in vacuo toremove DMF and to the residue was added water and the product wasextracted with EtOAc twice. The EtOAc extracts were dried (MgSO₄),filtered and concentrated. The residue was purified by silica gel columnchromatography eluting with 5% MeOH—CH₂Cl₂ to obtain 10 mg (0.021 mmol,Y. 19%) of the title compound Example 320 as amorphous powder: MS m/e488 (MH); ¹H NMR (CDCl₃) δ ppm 1.33, 1.36 (3H, 2d, J=7 Hz), 3.00 (3H, s,CH₃), 3-4.6 (8H, m, CH₂N), 4.05 (3H, s, CH₃O), 7.38-7.44 (5H, m, Ar-Hs),7.81 (1H, s), 8.02 (1H, s), 8.16, 8.17, 8.18, 8.19 (1H, 4s), 11.10 (1H,s, NH).

Preparation of 3-methyl-1,2,4-triazole (2-82)

Procedure:

A solid mixture of formic hydrazide (6.0 g, 0.1 mol; Aldrich) andthiopropionamide (8.92 g, 0.1 mol; TCI) was heated with stirring at 150°C. (oil bath temp.) for 2 hrs with a gentle stream of nitrogen. It wascooled and stored at room temperature overnight. The solid reactionmixture was suspended in 20% EtOAc/CH₂Cl₂, removing insoluble solid andthe filtrate was concentrated. The residue was purified by columnchromatography, eluting first with 50-80% EtOAc/CH₂Cl₂, removingby-products, and then with 10% MeOH/CH₂Cl₂, collecting 5.4 g (0.056 mol,Y. 56%) of the title compound as a solid: MS (ESI−) m/z 96 (M−H); ¹H NMR(CDCl₃) δ ppm 1.37 (3H, t, J=7.5 Hz), 2.88 (2H, q, J=7.5 Hz), 8.06 (1H,s, 5-H), 9.4 (1H, br, NH).

Reference: Vanek, T.; Velkova, V.; Gut, Jiri Coll. Czech. Chem. Comm.1985, 49, 2492.

Preparation of 3-82

Procedure:

A mixture of 4-methoxy-7-chloro-6-azaindole 2e (910 mg, 5 0 mmol),potassium carbonate (1.38 g, 10 mmol, 2 eq.), copper powder (635 mg, 10mmol, 2 eq.), and 3-ethyl-1,2,4-triazole (2.4 g, 25 mmol, 5 eq.) in asealed tube was heated at 145-150° C. (external oil bath temperature)for 52 h, by which time HPLC analysis indicated no more reactionprogressed. After cooling, MeOH was added, the insoluble material(copper powder) was filtered through a Celite pad, and rinsed withmethanol. The filtrate was concentrated in vacuo. The residue waspurified by silica gel column chromatography (50% EtOAc/CH₂Cl₂) toobtain 450 mg of the products as an about 4:1 mixture of tworegio-isomers. This was further separated by C-18 reverse phase silicagel (YMC, ODS-A 75 μm) eluted with 15% CH₃CN/H₂O containing 0.1% TFA.The fractions containing the major isomer were concentrated in vacuo toremove acetonitrile and the aqueous solution was extracted with CH2C12after neutralizing with aqueous sodium bicarbonate to obtain the titlecompound 3-82 (305 mg, 1.25 mmol; Y. 25%): HPLC >97% (AP at 254 nm); MS(LC/MS) m/z 244 (M+H); ¹H NMR (CDCl₃) δ ppm 1.43 (3H, t, J=7.5 Hz; CH₃),2.91 (2H, q, J=7.5 Hz; CH₂), 4.05 (3H, s, OCH₃), 6.71 (1H, dd, J=6, 2.4Hz, H-3), 7.57 (1H, t, J=3 Hz, H-2), 7.57 (1H, s, H-5), 9.16 (1H, s,triazole-H-5), 10.3 (1H, br, NH).

Preparation of 4-82

Procedure:

AlCl₃ (2.50 g, 18.8 mmol, 15 eq.) was dissolved in a solution of CH₂Cl₂(8 mL) and nitromethane (2 mL) under dry nitrogen. To this solution wasadded compound 3-82 (305 mg, 1.26 mmol) under stirring and under N₂,followed by methyl chlorooxoacetate (612 mg, 5.0 mol, 4 eq.). Themixture was stirred under N₂ at room temperature for 1.5 h. The mixturewas added drop-wise to a cold and stirred solution of 20% aqueousammonium acetate solution (120 mL). The mixture was stirred for 30 minand the resultant precipitate was filtered, washed thoroughly with waterand dried in vacuo to obtain 320 mg (0.97 mmol, Y. 77%) of the titlecompound 5-82 as a solid: HPLC purity 97% (AP at 254 nm); LC/MS m/z 330(M+H); ¹H NMR (DMSO-d₆) δ ppm 1.35 (3H, t, J=7.5 Hz, CH₃), 2.85 (2H, q,J=7.5 Hz, CH₂), 3.89 (3H, s, OCH₃), 3.99 (3H, s, OCH₃), 7.90 (1H, s,H-5), 8.35 (1H, s, H-2), 9.25 (1H, s, triazole-H-5), 12.4 (1H, brs, NH).

Preparation of 5-82

Procedure:

To a suspension of the methyl ester 4-82 (315 mg, 0.957 mmol) in MeOH (8mL) was added 0.25M NaOH solution in water (7.6 mL, 1.9 mmol, 2 eq.) atroom temperature and the mixture stirred for 15 min by which time HPLCindicated the hydrolysis was complete. The mixture was concentrated invacuo quickly to remove MeOH, and to the residual solution was addedwater (˜10 mL) and 1N HCl (2 mL) with stirring to neutralize themixture. The resultant fine precipitate was filtered, washed with waterand dried in vacuo to obtain 285 mg (0.904 mmol, Y. 94%) of the titlecompound 5-82 as off-white solid: HPLC purity >96% (AP at 254 nm); LC/MSm/z 316 (M+H); ¹H NMR (DMSO-d₆) δ ppm 1.35 (3H, t, J=7.5 Hz, Me), 2.85(2H, q, J=7.5 Hz, CH₂), 3.97 (3H, s, CH₃O), 7.88 (1H, s, H-5), 8.30 (1H,d, J=3 Hz, H-2), 9.24 (1H, s, triazole-H-5), 12.28 (1H, s, NH).

Preparation of Example 321

Procedure:

A mixture of the acid 5-82 (126 mg, 0 4 mmol) and HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphonate, 228 mg, 0.6 mmol; 1.5 eq.) in a mixture of CH₂Cl₂(2 mL) and DMF (2 mL) was stirred for 30 min under N₂. To this mixturewas added a mixture of benzoylpiperazine hydrochloride (136 mg, 0.60mmol; 1.5 eq.) and DMAP (dimethylaminipyridine, 147 mg, 1.2 mmol; 3 eq.)in DMF (2 mL), and the mixture ws stirred at room temperature under N₂for 15 min, by which time HPLC indicated the reaction was complete. Themixture was quickly concentrated in vacuo to remove DMF and all volatilematerials, and to the residue was added water (50 mL) under stirring andsonication. The precipitates formed were collected, washed with waterand dried in vacuo to obtain 160 mg (0.328 mmol, Y. 82%) of the titlecompound Example 321 as off-white solid: HPLC purity 100% (AP, at 254nm); LC/MS m/z 488 (M+H); ¹H NMR (DMSO-d6) δ ppm 1.35 (3H, t, J=7.5 Hz,Me), 2.85 (2H, q, J=7.5 Hz, CH₂), 3.43 (4H, br, CH₂N), 3.68 (4H, br,CH₂N), 4.00 (3H, s, CH₃O), 7.46 (5H, br. s, Ar-Hs), 7.89 (1H, s,indole-H-5), 8.26 (1H, s, indole-H-2), 9.25 (1H, s, triazole-H-5), 12.32(1H, br.s, NH).

Preparation of Example 322

Procedure:

A mixture of the acid 5-82 (79 mg, 0.25 mmol) and HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphonate, 142 mg, 0.375 mmol; 1.5 eq.) in a mixture ofCH₂Cl₂(1 mL) and DMF (1 mL) was stirred for 30 min under N₂. To thismixture was added a mixture of benzoylpiperazine hydrochloride (136 mg,0.60 mmol; 1.5 eq.) and DMAP (dimethylaminipyridine, 92 mg, 0.75 mmol; 3eq.) in DMF (1 mL), and the mixture was stirred at room temperatureunder N₂ for 15 min, by which time HPLC indicated the reaction wascomplete. The mixture was quickly concentrated in vacuo to remove allsolvents, CH₂Cl₂ and DMF, and to the residue was added water (˜25 mL)under stirring and sonication. The resultant gum were further washedwith water and collected by decantation. The residual gum was dried invacuo. The solution of this gum in isopropanol was concentrated in vavuoto remove any residual water. Addition of anhydrous diethyl ether andtrituaration gave 90 mg (0.18 mmol, Y. 72%) of the title compoundExample 322 as off-white solid: HPLC purity ˜95% (AP, at 254 nm); LC/MSm/z 502 (M+H); ¹H NMR (DMSO-d6) δ ppm 1.15, 1.22 (3H, 2d, J=6.6 Hz, Me),1.35 (3H, t, J=7.5 Hz, Me), 2.85 (2H, q, J=7.5 Hz, CH₂), 2.9-4.4 (7H, m,CH₂N, CHN), 3.99, 4.00 (3H, 2s, CH₃O), 7.45 (5H, br. s, Ph-Hs), 7.89(1H, s, indole-H-5), 8.20, 8.25 (1H, 2s, indole-H-2), 9.24, 9.25 (1H,2s, triazole-H-5), 12.29, 12.32 (1H, 2br.s, NH).

The following compounds, Example 323, and Example 324, were prepared bythe method described above using 3-(methoxymethyl)-1,2,4-triazole(10-83).

Synthetic Scheme

Preparation of 3-methoxymethyl-1,2,4-triazole (10-83)

Procedure:

To a mixture of methoxyacetonitrile (25 g, 0.35 mol: Aldrich) anddiethylamine (1 g, 8 6 mmol) was condensed H₂S (50 mL), and the mixturewas sealed, and heated at 50° C. for 14 hrs. After cooling volatilematerials were evaporated and the residue was dissolved in water,extracted with EtOAc several times. The combined organic extracts werewashed with brine, dried over anhydrous Na₂SO₄, and concentrated invacuo. The residue was purified by column chromatography(EtOAc:CH₂Cl₂=1:10) to obtain 13 g (0.12 mol, Y. 35%) of the titlecompound as a dark oil: GC/MS m/z 105 (M); ¹H NMR (CDCl₃) δ ppm 3.43(3H, s, CH₃), 4.26 (2H, s, CH₂).

Preparation of 3-methoxymethyl-1,2,4-triazole (10-83)

Procedure:

A solid mixture of formic hydrazide (4.58 g, 0.0763 mol) andmethoxythioacetamide (8.92 g, 0.1 mol) was heated with stirring at 150°C. (oil bath temp.) for 2 hrs with a gentle stream of nitrogen. It wascooled and stored at room temperature overnight. The solid reactionmixture was suspended in 20% EtOAc/CH2Cl2, removing insoluble solid andthe filtrate was concentrated. The residue was purified by columnchromatography, eluting first with 50-80% EtOAc/CH₂Cl₂, removingby-products, and then with 10% MeOH/CH₂Cl₂, collecting 3.8 g (0.034 mol,Y. 44%) of the title compound 10-83 as a solid: ¹H NMR (CDCl₃) δ ppm3.48 (3H, s, MeO), 4.67 (2H, s, CH₂), 8.10 (1H, s, 5-H).

Compound 11-83

Y. 9%: HPLC>98% (AP at 254 nm); MS (LC/MS) m/z 260 (M+H); ¹H NMR (CDCl₃)δ ppm 3.53 (3H, s, MeO), 4.06 (3H, s, 4-OCH₃), 4.69 (2H, s, CH₂), 6.73(1H, dd, J=3, 2.4 Hz, H-3), 7.40 (1H, t, J=2.7 Hz, H-2), 7.58 (1H, s,H-5), 9.16 (1H, s, triazole-H-5), 10.2 (1H, br, NH).

Compound 12-83

Y. 78%: HPLC 100% (AP at 254 nm); MS (LC/MS) m/z 346 (M+H); ¹H NMR(CD₃OD) δ ppm 3.51 (3H, s, MeO), 3.94 (3H, s, MeO), 4.05 (3H, s, MeO),4.71 (2H, s, CH₂), 7.87 (1H, s), 8.35 (1H, s), 9.33 (1H, s,triazole-H-5).

Compound 13-83

Y. 97%: HPLC 98% (AP at 254 nm); MS (LC/MS) m/z 332 (M+H); ¹H NMR(CDCl₃) δ ppm 3.49 (1H, s, OH), 3.55 (3H, s, MeO), 4.10 (3H, s, MeO),4.72 (2H, s, CH₂), 7.84 (1H, s, H-5), 9.13 (1H, d, J=3.3 Hz), 9.21 (1H,s, triazole-H-5), 11.15 (1H, br, NH).

Example 323

Y. 79%: HPLC 100% (AP at 254 nm); MS (LC/MS) m/z 504 (M+H); ¹H NMR(DMSO-d₆) δ ppm 3.39 (3H, s, MeO), 3.42 (4H, br, CH₂N), 3.68 (4H, br,CH₂N), 4.01 (3H, s, 4-MeO), 4.61 (2H, s, CH₂), 7.46 (5H, s, Ph-Hs), 7.92(1H, s), 8.27 (1H, s), 9.36 (1H, s, triazole-H-5), 12.42 (1H, br.s, NH).

Example 324

Y. 69%: HPLC >97% (AP at 254 nm); MS (LC/MS) m/z 518 (M+H); ¹H NMR(DMSO-d₆) δ ppm 1.15, 1.22 (3H, 2d, J=7 Hz, Me), 2.9-4.4 (7H, m, CH₂N,CHN), 3.39 (3H, s, MeO), 4.00, 4.01 (3H, 2s, CH₃O), 4.61 (2H, s, CH₂),7.4-7.5 (5H, m, Ph-Hs), 7.92 (1H, s, indole-H-5), 8.21, 8.29 (1H, 2s,indole-H-2), 9.35, 9.36 (1H, 2s, triazole-H-5), 12.4 (1H, br, NH).

The following compounds, Examples 325, 326, 327, and 328, were preparedby the method described above using 4-methyl-1,2,3-triazole (19-84).

Preparation of 4-methyl-1,2,3-triazole (19-84)

Procedure:

This compound 19-84 was prepared by the method described in M. BegtrupJ. Chem Soc., Perkin Transactions II, 1976, 736.

A mixture of m-nitrobenzoyl azide (38.4 g, 0.200 mol; prepared fromm-nitrobenzoyl chloride and sodium azide following the proceduredescribed in Org. Syn. Coll. Vol. IV, 1963, p. 715) and1-triphenylphosphoranylidene-2-propanone (63.6 g, 0.200 mol: Aldrich) inCH₂Cl₂ (300 mL) was stirred at room temperature for 2 hrs. The mixturewas concentrated in vacuo to obtain a solid. This solid was dissolved inMeOH, and the solution was stirred at room temperature for 30 min, andthe precipitates formed were removed. The filtrate was concentrated invacuo, and the residue was extracted with water (500 mL) containing TFA(17 mL). This solution was washed once with a small amount of CH₂Cl₂ toremove the most of triphenylphosphine, and the aqueous phase neutralizedwith NaHCO3 to pH 7 and extracted five times with CH₂Cl₂ (total of 500mL). The combined extracts were dried over Na2SO4, concentrated toobtain 7.6 g (0.091 mol, Y. 46%) of the title compound 19-84 as a yellowoil: ¹H NMR (CDCl₃) δ ppm 2.37 (3H, s, Me), 7.50 (1H, s, 5-H), 10.41(1H, br, NH).

Compound 20-84

Yield 5-9%: HPLC purity 100% (RT 1.89 min, AP at 254 nm); MS (LC/MS) m/z230 (M+H); ¹H NMR (CDCl₃) δ ppm 2.47 (3H, s, Me), 4.07 (3H, s, 4-OCH₃),6.74 (1H, t, J=2.7 Hz, H-3), 7.42 (1H, t, J=2.7 Hz, H-2), 7.62 (1H, s,H-5), 8.41 (1H, s, triazole-H-5), 10.3 (1H, br, NH).

The structure was confirmed by a single X-ray crystallographic analysis.

Compound 21-84

Yield 11-14%: HPLC purity 100% (RT 1.36 min, AP at 254 nm); MS (LC/MS)m/z 230 (M+H); ¹H NMR (CDCl₃) δ ppm 2.48 (3H, s, Me), 4.06 (3H, s,4-OCH₃), 6.74 (1H, dd, J=3, 2.4 Hz, H-3), 7.39 (1H, t, J=3 Hz, H-2),7.68 (1H, s, H-5), 7.72 (1H, br, triazole-H-5), 10.25 (1H, br, NH).

Compound 22-84

Yield 79%: HPLC purity 94% (AP at 254 nm); MS (LC/MS) m/z 316 (M+H); ¹HNMR (CDCl₃) δ ppm 2.49 (3H, s, Me), 3.96 (3H, s, OMe), 4.07 (3H, s,OMe), 7.81 (1H, s, H-5), 8.38 (1H, d, J=3.3 Hz, H-2), 8.42 (1H, s,triazole-H-5), 11.07 (1H, br, NH).

Compound 23-84

Yield 81%: HPLC purity >95% (AP at 254 nm); MS (LC/MS) m/z 316 (M+H); ¹HNMR (CDCl₃) δ ppm 2.49 (3H, s, Me), 4.00 (3H, s, OMe), 4.05 (3H, s,OMe), 7.72 (1H, s, H-5), 7.89 (1H, br.s, triazole-H-5), 8.33 (1H, d, J=3Hz, H-2), 11 (1H, br, NH).

Compound 24-84

Yield 83%: HPLC purity 98% (AP at 254 nm); MS (LC/MS) m/z 302 (M+H); ¹HNMR (CD3OD) δ ppm 2.46 (3H, s, Me), 4.06 (3H, s, OMe), 7.89 (1H, s,H-5), 8.39 (1H, d, J=3.3 Hz, H-2), 8.58 (1H, s, triazole-H-5).

Compound 25-84

Yield 74%: HPLC purity 100% (AP at 254 nm); MS (LC/MS) m/z 302 (M+H); ¹HNMR (CD₃OD) δ ppm 2.50 (3H, s, Me), 4.05 (3H, s, OMe), 7.84 (1H, s),7.90 (1H, s), 8.39 (1H, s).

Example 325

Y. 76%: HPLC 98% (AP at 254 nm); MS (LC/MS) m/z 474 (M+H); ¹H NMR(DMSO-d₆) δ ppm 2.40 (3H, s, Me), 3.44 (4H, br, CH₂N), 3.68 (4H, br,CH₂N), 4.02 (3H, s, 4-MeO), 7.46 (5H, s, Ph-Hs), 7.96 (1H, s), 8.21 (1H,s), 8.68 (1H, s, triazole-H-5), 12.72 (1H, br.s, NH).

Example 326

Y. 62%: HPLC 97% (AP at 254 nm); MS (LC/MS) m/z 488 (M+H); ¹H NMR(DMSO-d₆) δ ppm 1.14, 1.21 (3H, 2d, J=7 Hz, Me), 2.40 (3H, s, Me),2.9-4.4 (7H, m, CH₂N, CHN), 4.01, 4.02 (3H, 2s, CH₃O), 7.46 (5H, s,Ph-Hs), 7.96 (1H, s), 8.16, 8.23 (1H, 2s), 8.675, 8.68 (1H, 2d, J=2.5Hz), 12.72 (1H, br.s, NH).

Compound Example 327

Y. 73%: HPLC 96% (AP at 254 nm); MS (LC/MS) m/z 474 (M+H); ¹H NMR(DMSO-d₆) δ ppm 2.45 (3H, s, Me), 3.44 (4H, br, CH₂N), 3.68 (4H, br,CH₂N), 4.01 (3H, s, 4-MeO), 7.46 (5H, s, Ph-Hs), 7.93 (1H, s), 8.04 (1H,s), 8.24 (1H, d, J=3 Hz, H-2), 12.51 (1H, br.s, NH).

Example 328

Y. 74%: HPLC 99% (AP at 254 nm); MS (LC/MS) m/z 488 (M+H); ¹H NMR(DMSO-d₆) δ ppm 1.15, 1.22 (3H, 2d, J=7 Hz, Me), 2.45 (3H, s, Me),2.9-4.4 (7H, m, CH₂N, CHN), 4.00, 4.01 (3H, 2s, CH₃O), 7.45 (5H, s,Ph-Hs), 7.92 (1H, s), 8.03 (1H, s), 8.18, 8.26 (1H, 2s), 12.5 (1H, br.s,NH).

Preparation of Example 329

A mixture of compound 5b (128 mg, 0.3 mmol), imidazole-4-propionic acid(1.26 g, 9 mmol; 30 eq.; prepared from urocanic acid by catalytichydrogenation using 10% Pd-C in acetic acid, following the proceduredescribed in J. Altman, N. Shoef, M. Wilchek, and A. Warshawsky J. Chem.Soc., Perkin Trans. I, 1984, 59), copper powder (38 mg, 0 6 mmol; 2eq.), potassium carbonate (83 mg, 0.6 mmol; 2 eq.) was flushed withanhydrous nitrogen and heated in a sealed tube at 190°-200° C. (oil bathtemp.) for 2 h. Upon cooling, to the mixture was added MeOH, and theinsoluble material was filtered. The filtrate was concentrated in vacuoand purified by C-18 reverse phase column (YMC, eluting with 15%CH₃CN-water containing 0.1% TFA) to obtain 12 mg (0.023 mmol, Y. 7.5%)of the title compound Example 329 as amorphous powder (about 1:1 mixtureof two regio-isomers): HPLC purity 96% (AP, at 254 nm); MS (LC/MS) m/z531 (M+H); ¹H NMR (CD₃OD) δ ppm 2.74, 3.00 (2H, 2t, J=7 Hz), 2.82, 3.11(2H, 2t, J=7 Hz), 3.59 (4H, br, CH₂N), 3.79 (4H, br, CH₂N), 3.79, 4.10(3H, 2s, CH₃O), 6.73 (s), 7.33 (s), 7.48 (5H, br. s, Ar-Hs), 7.93(br.s), 8.00 (s), 8.10 (s), 8.40 (s), 8.77 (s), 9.43 (br.s).

The following compounds, Examples 330 and 331 were similarly prepared byfollowing the above procedure.

Example 330

Y. 10% (150° C., 7 h): HPLC 93% (AP at 254 nm); MS (LC/MS) m/z 485(M+H); ¹H NMR (CD₃OD, 500 MHz) δ ppm 3.63 (4H, br, CH₂N), 3.84 (4H, br,CH₂N), 4.05 (3H, s, 4-MeO), 7.32 (2H, m, pyr-Hs), 7.52 (5H, s, Ph-Hs),7.71 (1H, s), 8.06 (1H, t, J=7.5 Hz, pyr-H), 8.48 (1H, d, J=4.5 Hz),8.60 (1H, s).

Example 331

Y. 10% (150° C., 7 h): HPLC 93% (AP at 254 nm); MS (LC/MS) m/z 563(M+H); ¹H NMR (CDCl₃) δ ppm 2.76 (3 h. S, Me), 3.55 (4H, br, CH₂N), 3.78(4H, br, CH₂N), 4.09 (3H, s, 4-MeO), 6.71 (1H, t, J=7 Hz, pyr-H), 7.43(5H, s, Ph-Hs), 7.68 (1H, t, J=7 Hz, pyr-H), 7.82 (1H, t, J=7 Hz,pyr-H), 7.91 (1H, s), 8.15 (1H, s), 10.84 (1H, br, NH).

A mixture of precursor 5w (71.5 mg, 0.17 mmol) in MeOH (1.5 mL) wascooled to 0° C., and saturated with hydrogen chloride gas over thecourse of 10 min. The volatiles were then evaporated via blowing N₂overnight to provide precursor 5wa. ¹H NMR: (DMSO-d₆) δ 12.45 (s, 1H),8.12 (s, 2H), 8.07 (s, 1H), 7.65 (s, 1H), 7.45 (s, 5H), 4.04 (s, 3H),3.80-3.30 (b m, 8H); LC/MS: (ES+) m/z (M+H)⁺ =436, HPLC R_(t)=1.357(Column G).

To a mixture of precursor 5wa (10 mg, 23 μmol) in acetic acid (0.4 mL)and acetic anhydride (0.75 mL) at 0° C., was added NaNO₂ (30 mg, 0.43mmol). The reaction mixture was stirred at 0° C. for 30 min, and allowedto warm to ambient temperature. After stirring for an additional 1.5 hr,the mixture was filtered and the residue dried under vacuum to give thedesired compound 5wb an off-white solid. ¹H NMR: (CD₃OD) δ 8.44 (s, 1H),8.08 (s, 1H), 7.48 (b s, 5H), 4.14-3.27 (m, 8H), 4.14 (s, 3H); LC/MS:(ES+) m/z (M+H)⁺ =437, HPLC R_(t)=0.750 (Column G).

A flask was charged with precursor 5wb (2.6 mg, 6.0 μmol), DMF (0.5 mL),tert-butyl carbazate (1.2 mg, 8.9 μmol), DEPBT (5.4 mg, 18 μmol), andN,N-diisopropylethylamine (10 μL, 30 μmol). The reaction mixture wasallowed to stir at ambient temperature overnight. The product 5wc wasseparated using the following reverse phase preparative HPLC method:Start % B=0, Final % B=100, Gradient time=6 min, Flow Rate=30 mL/min,Column: Xerra Prep MS C18 5 μm 19×50 mm, Fraction Collection: 4.38-4.59min. ¹H NMR: (CD₃OD) δ 8.29 (s, 1H), 8.11 (s, 1H), 7.47 (b s, 5H),4.11-3.28 (m, 8H), 4.10 (s, 3H), 1.50 (b s, 9H); LC/MS: (ES+) m/z (M+H)⁺=551, HPLC R_(t)=1.203 (Column G).

To precursor 5wc (57 mg, 0.104 mmol) was added a solution of HCl in1,4-dioxane (4 M, 0.25 mL), and the reaction mixture was stirredovernight at room temperature. The deprotection afforded the desiredproduct precursor 5wd cleanly. The excess reagent and solvent wereevaporated via blowing N₂, and the product dried under vacuum. LC/MS:(ES+) m/z (M+H)⁺ =451, HPLC R_(t)=0.803 (Column G).

A solution of precursor 5we (106 mg, 0.25 mmol) in MeOH (2.5 mL) in asealed tube at 0° C. was flushed with N₂, and saturated with HCl gas for10 min. The tube was closed and the reaction mixture was stirred at 70°C. for 50 minutes. After cooling to ambient temperature, the volatileswere evaporated in vacuo to give precursor 5wf. ¹H NMR: (CD₃OD) δ 8.33,8.30 (s, 1H), 8.13, 8.12 (s, 1H), 7.48-7.44 (m, 5H), 4.60-3.10 (b m,7H), 4.12, 4.11 (s, 3H) 4.06 (s, 3H), 1.35, 1.29 (d, J=6.5, 7.0, 3H);LC/MS: (ES+) m/z (M+H)⁺ =465, HPLC R_(t)=0.993 (Column G).

To a solution of precursor 5wf (65 mg, 0.14 mmol) in MeOH (1 mL) wasadded NaOH (1.5 mL, 1 N aq.). The mixture was stirred for 2 hours, andupon which time HCl (1.5 mL, 1 N aq.) was added to quench the reaction.The volatiles were evaporated in vacuo to give precursor 5wg. ¹H NMR:(TFA solvate, CD₃OD) δ 8.54, 8.51 (s, 1H), 8.11 (b s, 1H), 7.57-7.48 (bs, 5H), 4.60-3.10 (b m, 7H), 4.17, 4.16 (s, 3H), 1.37, 1.33 (d, J=6.5,6.0, 3H); LC/MS: (ES+) m/z (M+H)⁺ =451, HPLC R_(t)=0.837 (Column G).

To a mixture of precursor 5wg (22 mg, 0.048 mmol) in DMF (1 mL) wereadded tert-butyl carbazate (14 mg, 0.11 mmol), DEPBT (53 mg, 0.18 mmol),and N,N-diisopropylethylamine (40 μL, 0.23 mmol). The reaction mixturewas stirred overnight, and the desired compound precursor 5wh wasisolated via preparative reverse phase HPLC using the followingconditions: Start % B=0, Final % B=100, Gradient time=6 min, FlowRate=30 mL/min, Column: Xerra Prep MS C18 5 μm 19×50 mm, FractionCollection: 4.37-4.98 min. ¹H NMR: (CD₃OD) δ 8.28, 8.26 (s, 1H), 8.08 (bs, 1H), 7.47-7.43 (m, 5H), 4.75-3.26 (m, 7H), 4.10 (s, 3H), 1.50 (b s,9H), 1.36-1.27 (m, 3H); LC/MS: (ES+) m/z (M+H)⁺ =565, HPLC R_(t)=1.207(Column G).

A mixture of precursor 5wh in a solution of HCl in 1,4-dioxane (0.2 mL,4 M) was stirred for 3.5 hr at ambient temperature. The volatiles wereevaporated in vacuo, and the crude mixture was purified via reversephase preparative HPLC using the following method: Start % B=0, Final %B=100, Gradient time=6 min, Flow Rate=30 mL/min, Column: Xerra Prep MSC18 5 μm 19×50 mm, Fraction Collection: 3.20-3.80 min. ¹H NMR: (CD₃OD) δ8.74, 8.71 (s, 1H), 8.31, 8.28 (s, 1H), 7.47-7.44 (m, 5H), 4.46-3.35 (m,7H), 4.18, 4.10 (s, 3H), 1.38-1.22 (m, 3H); LC/MS: (ES+) m/z (M+H)⁺=465, HPLC R_(t)=0.850 (Column G).

Example 333 and Example 334

Thioacetamide (2 mg, 22 μmol) was added to Example 333 (10 mg, 20 mol,HCl salt) in a round-bottom flask. The mixture was heated to 150° C. for20 minutes, after which it was cooled to ambient temperature, anddiluted with MeOH. Purification of the desired compound Example 334 wasperformed via preparative reverse phase HPLC using the following method:Start % B=0, Final % B=100, Gradient time=6 min, Flow Rate=30 mL/min,Column: Xerra Prep MS C18 5 μm 19×50 mm, Fraction Collection: 3.47-3.86min. ¹H NMR: (CD₃OD) δ 8.64, 8.62 (s, 1H), 8.04 (b s, 1H), 7.49-7.44 (m,5H), 4.37-3.44 (m, 7H), 4.16, 4.14 (s, 3H), 2.63 (s, 3H), 1.36-1.32 (m,3H); LC/MS: (ES+) m/z (M+H)⁺ =488, HPLC R_(t)=0.973 (column G).

The following examples were prepared in a similar manner as above.

Example 335

Preparation of Example 335

¹H NMR: (CD₃OD) δ 8.60, 8.58 (s, 1H), 8.12 (d, J=3, 1H), 7.71-7.67 (m,1H), 7.59-7.54 (m, 4H), 7.50-7.46 (m, 5H), 4.37-3.44 (m, 7H), 4.16, 4.14(s, 3H), 1.37, 1.33 (d, J=6.5, 3H); LC/MS: (ES+) m/z (M+H)⁺ =550, HPLCR_(t)=1.283 (column G).

Example 336

¹H NMR: (CD₃OD) δ 8.66, 8.64 (s, 1H), 8.04 (d, J=3, 1H), 7.49-7.40 (m,5H), 4.41-3.44 (m, 7H), 4.16, 4.14 (s, 3H), 3.00 (q, J=7.5, 2H), 1.46(t, J=7.5, 3H), 1.36-1.32 (m, 3H); LC/MS: (ES+) m/z (M+H)⁺ =502, HPLCR_(t)=1.007 (column G).

Example 337

¹H NMR: (CD₃OD) δ 8.59, 8.57 (s, 1H), 8.11 (b d, 1H), 7.48-7.40 (m, 9H),4.46-3.39 (m, 7H), 4.16, 4.14 (s, 3H), 2.45 (s, 3H), 1.40-1.29 (m, 3H);LC/MS: (ES+) m/z (M+H)⁺ =564, HPLC R_(t)=1.363 (column G).

Example 338

¹H NMR: (CD₃OD) δ 9.62 (s, 1H), 9.11 (s, 1H), 8.82 (d, J=5.5, 1H), 8.47(d, J=8.5, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 7.49-7.46 (m, 5H), 4.64-3.35(m, 7H), 4.14, 4.13 (s, 3H), 1.37, 1.32 (d, J=7, 3H); LC/MS: (ES+) m/z(M+H)⁺ =551, HPLC R_(t)=1.090 (column G).

Example 339

¹H NMR: (CD₃OD) δ 8.50 (s, 1H), 8.17 (b d, 1H), 7.53-7.45 (m, 9H),4.64-3.35 (m, 7H), 4.14, 4.13 (s, 3H), 1.37, 1.32 (d, J=6.5, 7, 3H);LC/MS: (ES+) m/z (M+H)⁺ =584, HPLC R_(t)=1.427 (column G).

Example 340

¹H NMR: (CD₃OD) δ 8.56, 8.55 (s, 1H), 8.36 (s, 1H), 8.10 (s, 1H), 7.72(s, 1H), 7.48-7.45 (m, 5H), 7.09 (s, 1H), 4.64-3.44 (m, 7H), 4.15, 4.14(s, 3H), 1.36-1.32 (m, 3H); LC/MS: (ES+) m/z (M+H)⁺ =540, HPLCR_(t)=1.133 (column G).

Example 341

¹H NMR: (CD₃OD) δ 8.54, 8.51 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H),7.48-7.39 (m, 5H), 4.71-3.44 (m, 7H), 4.14, 4.13 (s, 3H), 2.85 (s, 3H),1.37-1.29 (m, 3H); LC/MS: (ES+) m/z (M+H)⁺ =571, HPLC R_(t)=1.450(column G).

Example 342

¹H NMR: (CD₃OD) δ 8.64 (s, 1H), 8.04 (s, 1H), 7.48 (s, 5H), 4.16 (s,3H), 3.92-3.39 (m, 8H), 2.64 (s, 3H); LC/MS: (ES+) m/z (M+H)⁺ =474, HPLCR_(t)=0.903 (column G).

Examples 343 and 344

Precursor 5b (60 mg, 0.14 mmol), 4-fluoropyrazole (0.30 mL) (prepared asdescribed in Molines, H.; Wakselman, C. J. Org. Chem. 1989, 54,5618-5620), copper(0) (8.0 mg, 0.13 mmol), K₂CO₃ (15 mg, 0.11 mmol) andEtOH (0.30 mL) were combined in a sealed tube flushed with nitrogen andheated at 170° C. with microwave irradiation for 1.5 h. The reaction wascooled, filtered and concentrated. The residue was purified bypreparative HPLC under the standard conditions described above toprovide (6.6 mg, 0.014 mmol) of Example 343 as a yellow solid andExample 344 (3.1 mg. 0.006 mmol) as a greenish solid.

Example 343: ¹H NMR (500 MHz, CD₃OD) δ 8.56 (d, J=4.3 Hz, 1H), 8.27 (s,1H), 7.82-7.79 (m, 2H), 7.47 (br s, 5H), 4.03 (s, 3H), 3.97-3.45 (m,8H). MS m/z: (M+H)⁺ calcd for C₂₄H₂₁FN₆O₂: 477.16. found 477.16. HPLCretention time: 1.45 minutes (column G).

Example 344: ¹H NMR (500 MHz, CDCl₃) δ 11.16 (br s, 1H), 8.59 (s 1H),8.19 (s, 1H), 7.78-7.62 (m, 2H), 7.43 (br s, 5H), 4.04 (s, 3H),3.987-3.40 (m, 8H). MS m/z: (M+H)⁺ calcd for C₂₄H₂₁ClN₆O₂: 493.13. found493.12. HPLC retention time: 1.59 minutes (column G).

Example 353

Example 353 was prepared from the corresponding 7-chloro precursor 5mnand 2-tributyl stannyl oxazole via the standard Stille couplingconditions described above. The 7-chloro precursor was preparedsimilarly to precursor 5d except that 2-(R) methyl piperazine benzamide(precursor 17b) was utilized. Example 353, 4-azaindole-7-(2′-oxazole):¹H NMR (500 MHz, CD₃OD) δ 8.68 (s, 0.5H), 8.67 (s, 0.5H), 8.45 (s,0.5H), 8.43 (s, 0.5H), 8.18 (s, 1H), 7.86 (d, J=4.9 Hz, 0.5H), 7.85 (d,J=4.9 Hz, 0.5H), 7.55 (s, 1H), 7.50-7.40 (m, 5H), 4.45-3.06 (m, 7H),1.48 (d, J=6.7 Hz, 1.5H) 1.24 (d, J=6.7 Hz, 1.5H). MS m/z: (M+H)⁺ calcdfor C₂₄H₂₂N₅O₄: 444.16. found 444.23. HPLC retention time: 0.90 minutes(column G).

Example 354

Example 354 was prepared from the corresponding 7-chloro precursor 5mnand 2-tributyl stannyl thiazole via the standard Stille couplingconditions described above. The 7-chloro precursor was preparedsimilarly to precursor 5d except that 2-(R) methyl piperazine benzamide(precursor 17b) was utilized. Example 354: 4-azaindole-7-(2′-thiazole):¹H NMR (500 MHz, CD₃OD) δ 8.80 (s, 0.5H), 8.74-8.71 (m, 1.5H), 8.35 (d,J=3.5 Hz, 0.5H), 8.35 (d, J=3.5 Hz, 0.5H), 8.26 (d, J=3.5 Hz, 0.5H),8.25 (d, J=3.5 Hz, 0.5H), 8.14 (d, J=3.1 Hz, 0.5H), 8.14 (d, J=3.1 Hz,0.5H), 7.50-7.42 (m, 5H), 4.48-3.08 (m, 7H), 1.36 (d, J=6.7 Hz, 1.5H)1.32 (d, J=6.7 Hz, 1.5H). MS m/z: (M+H)⁺ calcd for C₂₄H₂₂N₅O₃S: 460.14.found 460.20. HPLC retention time: 0.94 minutes (column G).

Example 355

Example 355 was prepared via the procedure used for Example 205 from thecorresponding 7-chloro precursor 5mn and 1,2,3,triazole. The 7-chloroprecursor was prepared similarly to precursor 5d except that 2-(R)methyl piperazine benzamide (precursor 17b) was utilized. Example 355,4-azaindole-7-(2′-triazole): ¹H NMR (500 MHz, CD₃OD) δ 8.79-8.76 (m,1H), 8.78 (s, 0.5H), 8.70 (s, 0.5H), 8.44 (d, J=5.9 Hz, 0.5H), 8.43 (d,J=5.9 Hz, 0.5H), 8.38 (s, 1H), 8.38 (s, 1H), 7.51-7.42 (m, 5H),4.50-3.21 (m, 7H), 1.37 (d, J=6.7 Hz, 1.5H) 1.32 (d, J=6.7 Hz, 1.5H). MSm/z: (M+H)⁺ calcd for C₂₃H₂₂N₇O₃: 444.17. found 444.26. HPLC retentiontime: 0.90 minutes (column G).

Example 356

Example 356 was prepared via the procedure used for Example 205 from thecorresponding 7-chloro precursor 5mn and 3-methyl pyrazole. The 7-chloroprecursor was prepared similarly to precursor 5d except that 2-(R)methyl piperazine benzamide (precursor 17b) was utilized. Example 356,4-azaindole-7-(3′-methyl-2′-pyrazole): ¹H NMR (500 MHz, CD₃OD) δ8.73-8.71 (m, 1H), 8.70 (s, 0.5H), 8.63 (s, 0.5H), 8.64-8.60 (m, 1H),8.06 (s, 0.5H), 8.04 (s, 0.5H), 7.52-7.42 (m, 5H), 6.68 (s, 0.5H), 6.67(s, 0.5H), 4.61-3.21 (m, 7H), 2.51 (s, 3H), 1.35 (d, J=6.5 Hz, 1.5H)1.32 (d, J=6.5 Hz, 1.5H). MS m/z: (M+H)⁺ calcd for C₂₅H₂₅N₆O₃: 457.19.found 457.33. HPLC retention time: 1.04 minutes (column G).

Biology

-   -   “μM” means micromolar;    -   “mL” means milliliter;    -   “μl” means microliter;    -   “mg” means milligram;

The materials and experimental procedures used to obtain the resultsreported in Tables 1-5 are described below.

Cells:

-   -   Virus production—Human embryonic Kidney cell line, 293,        propagated in Dulbecco's Modified Eagle Medium (Life        Technologies, Gaithersburg, Md.) containing 10% fetal Bovine        serum (FBS, Sigma, St. Louis, Mo.).    -   Virus infection—Human epithelial cell line, HeLa, expressing the        HIV-1 receptors CD4 and CCRS was propagated in Dulbecco's        Modified Eagle Medium (Life Technologies, Gaithersburg, Md.)        containing 10% fetal Bovine serum (FBS, Sigma, St. Louis, Mo.)        and supplemented with 0.2 mg/mL Geneticin (Life Technologies,        Gaithersburg, Md.) and 0.4 mg/mL Zeocin (Invitrogen, Carlsbad,        Calif.).

Virus—Single-round infectious reporter virus was produced byco-transfecting human embryonic Kidney 293 cells with an HIV-1 envelopeDNA expression vector and a proviral cDNA containing an envelopedeletion mutation and the luciferase reporter gene inserted in place ofHIV-1 nef sequences (Chen et al, Ref 41). Transfections were performedusing lipofectAMINE PLUS reagent as described by the manufacturer (LifeTechnologies, Gaithersburg, Md.).

Experiment

-   1. Compound was added to HeLa CD4 CCRS cells plated in 96 well    plates at a cell density of 5×10⁴ cells per well in 100 μl    Dulbecco's Modified Eagle Medium containing 10% fetal Bovine serum    at a concentration of <20 μM.-   2. 100 μl of single-round infectious reporter virus in Dulbecco's    Modified Eagle Medium was then added to the plated cells and    compound at an approximate multiplicity of infection (MOI) of 0.01,    resulting in a final volume of 200 μl per well and a final compound    concentration of <10 μM.-   3. Samples were harvested 72 h after infection.-   4. Viral infection was monitored by measuring luciferase expression    from viral DNA in the infected cells using a luciferase reporter    gene assay kit (Roche Molecular Biochemicals, Indianapolis, Ind.).    Infected cell supernatants were removed and 50 μl of Dulbecco's    Modified Eagle Medium (without phenol red) and 50 μl of luciferase    assay reagent reconstituted as described by the manufacturer (Roche    Molecular Biochemicals, Indianapolis, Ind.) was added per well.    Luciferase activity was then quantified by measuring luminescence    using a Wallac microbeta scintillation counter.-   5. The percent inhibition for each compound was calculated by    quantifying the level of luciferase expression in cells infected in    the presence of each compound as a percentage of that observed for    cells infected in the absence of compound and subtracting such a    determined value from 100.-   6. An EC₅₀ provides a method for comparing the antiviral potency of    the compounds of this invention. The effective concentration for    fifty percent inhibition (EC₅₀) was calculated with the Microsoft    Excel Xlfit curve fitting software. For each compound, curves were    generated from percent inhibition calculated at 10 different    concentrations by using a four paramenter logistic model (model    205). The EC₅₀ data for the compounds is shown in Tables 2-4. Table    1 is the key for the data in Tables 2-4.

Cytoxicity assays were conducted with the same HeLa using methodologywell known in the art. This method has been described in the literature(S Weislow, R Kiser, D L Fine, J Bader, R H Shoemaker and M R Boyd: Newsoluble-formazan assay for HIV-1 cytopathic effects: application tohigh-flux screening of synthetic and natural products for AIDS-antiviralactivity. Journal of the National Cancer Institute. 81(8):577-586, 1989.

Cells were incubated in the presence of drug for six days, after whichcell viability was measured using a dye reduction assay (MTT) anddetermined as a CC50. This assay measures the intracellular reducingactivity present in actively respiring cells.

Results

TABLE 1 Biological Data Key for EC₅₀s Compounds with Compounds*Compounds EC50 > 50 nM but with with EC₅₀s > not yet tested at CompoundsEC₅₀s > 1 μM higher with 5 μM but < 5 μM concentrations EC50 < 1 μMGroup C Group B Group A′ Group A *Some of these compounds may have beentested at a concentration lower than their EC₅₀ but showed some abilityto cause inhibition and thus should be evaluated at a higherconcentration to determine the exact EC₅₀.

In Tables 2-5, X₂, X₄ etc. indicates the point of attachment.

TABLE 2

Examples EC₅₀ Table Entry Group (Example from Number.) R2 R3 R4 R9 ATable 1  1 (Example 1) H H

CH₃

A  2 (Example 2) H H

CH₃

A  4 (Example 4) H H

H

A  5 (Example 5) H H

CH₃

A  6 (Example 6) H H

CH₃

A  7 (Example 7) H H

H

A  8 (Example 8) H H

H

A  9 (Example 9) H H

CH₃

A  10 (Example 16) H H

CH₃

A  11 (Example 17) H H

H

A  12 (Example 18) H H

CH₃

A  13 (Example 10) H H

H

A  14 (Example 19) H H

H

A  15 (Example 11) H H

H

A′  16 (Example 20) H H

CH₃

A  17 (Example 21) H H

H

A  18 (Example 22) OMe H

H

A  19 (Example 23) OMe H

H

A  20 (Example 24) OMe H

H

A  21 (Example 25) OMe H

H

A  22 (Example 26) OMe H

H

A  23 (Example 27) OMe H

H

A  24 (Example 28) OMe H

H

A  25 (Example 29) F H

H

A  26 (Example 30) F H

H

A  27 (Example 15) OMe H

H

A  28 (Example 32) OMe H

H

A  29 (Example 33) H H

Me

A  30 (Example 34) H H

H

A  31 (Example 35) OMe H

H

A  32 (Example 36) OMe H

H

A  33 (Example 37) F H

Me

A  34 (Example 38) F H

H

A  35 (Example 39) OMe H

H

A  36 (Example 40) OMe H

H

A  37 (Example 41) F H

Me

A  38 (Example 42) F H

H

A  41 (Example 45) OMe H

H

A  42 (Example 46) OMe H

H

A  43 (Example 47) OMe H

H

A  45 (Example 49) OMe H

H

A  46 (Example 13) OMe H

H

A  47 (Example 55) OMe H

H

A  48 (Example 50) OMe H

H

A  49 (Example 14) OMe H

H

A  50 (Example 68) OMe H

H

A  51 (Example 69) OMe H

H

A  52 (Example 70) OMe H

H

A  53 (Example 71) OMe H

H

A  54 (Example 72) OMe H

H

A  55 (Example 82) OMe H

H

A  56 (Example 73) OMe H

H

A  57 (Example 83) OMe H

H

A  58 (Example 84) OMe H

H

A  59 (Example 85) OMe H

H

A  60 (Example 74) OMe H

H

A  61 (Example 75) OMe H

H

A  62 (Example 76) OMe H

H

A  63 (Example 77) OMe H

H

A  64 (Example 78) OMe H

H

A  65 (Example 80) OMe H

H

A  66 (Example 79) OMe H

H

A  67 (Example 87) OMe H

H

A  68 (Example 81) OMe H

H

A  69 (Example 88) OMe H

H

A  70 (Example 89) H H

H

A  71 (Example 90) OMe H

H

A  72 (Example 91) OMe H

H

A  72 (Example 92) OMe H

H

A  73 (Example 93) OMe H

H

A  74 (Example 94) OMe H

H

A  75 (Example 95) F H

H

A  76 (Example 96) Cl H

H

A  77 (Example 97) OMe H

H

A  78 (Example 98) OMe H

H

A  79 (Example 99) OMe H

H

A  80 (Example 100) OMe H

H

A  81 (Example 101) OMe H

H

A  82 (Example 102) OMe H

H

A  83 (Example 103) OMe H

H

A  84 (Example 104) OMe H

H

A  85 (Example 105) H H

(R)—Me

A  86 (Example 106) H H

(S)—Me

A  87 (Example 107) H H

(R)—Me

A  88 (Example 108) H H

(R)—Me

A  89 (Example 109) H H

(R)—Me

A  90 (Example 110) H H

(S)—Me

A  91 (Example 111) H H

(R)—Me

A  92 (Example 112) H H

(R)—Me

A  93 (Example 113) H H

(R)—Me

A  94 (Example 114) H H

(R)—Me

A  95 (Example 115) OMe H

H

A  96 (Example 116) OMe H

H

A  97 (Example 117) OMe H

H

A  98 (Example 118) OMe H

H

A  99 (Example 119) OMe H

H

A 100 (Example 120) OMe H

H

A 101 (Example 121) H H

(R)—Me

A 102 (Example 121-2) H H

(R)—Me

A 103 (Example 122) H H

(R)—Me

A 104 (Example 123) H H

(R)—Me

A 105 (Example 124) H H

(R)—Me

A 106 (Example 125) F H

H

A 107 (Example 138) OMe H

H

A 108 (Example 139) Br H

(R)—Me

A 109 (Example 140) F H

H

A 110 (Example 141) F H

(R)—Me

A 111 112 (Example 143) Cl H

H

A 113 (Example 144) Cl H

H

A 114 (Example 145) F H

H

A 115 (Example 146) F H

H

A 116 (Example 147) F H

H

A 117 (Example 148) F H

H

A 118 (Example 149) Cl H

H

A 119 (Example 150) H H

(R)—Me

A 120 (Example 151) OMe H

H

A 121 (Example 152) Cl H

H

A 122 (Example 153) H H

(R)—Me

A 123 (Example 154) F H

H

A 124 (Example 155) OMe H

H

A 125 (Example 156) OMe H

H

A 126 (Example 157) H H

(R)—Me

A 127 (Example 165) Cl H

H

A 128 (Example 166) F H

H

129 (Example 167) F H

H

130 (Example 162) H H

(R)—Me

A 131 (Example 163) Cl H

H

A 132 (Example 164) H H

(R)Me

A 133 (Example 169) OMe H

H

134 (Precursor 5t) OMe H

H

A 135 (Example 170) H H

(R)—Me

A 136 (Example 171) OMe H

H

A 137 (Example 172) OMe H

H

A 138 (Example 173) OMe H

H

A 139 (Example 174) OMe H

H

A 140 (Example 175) OMe H

H

A 141 (Example 176) OMe H

H

A 142 (Example 177) OMe H

H

A 143 (Example 178) OMe H

H

A 144 (Example 179) OMe H

H

A 145 (Example 180) OMe H

H

A 146 (Example 181) OMe H

H

A 147 (Example 182) OMe H

H

A 148 (Example 183) OMe H

H

A 149 (Example 184) OMe H

H

A 150 (Example 185) OMe H

H

A 151 (Example 186) OMe H

H

A 152 (Example 187) OMe H

H

A 153 (Example 188) OMe H

H

A 154 (Example 189) OMe H

H

A 155 (Example 190) OMe H

H

A 156 (Example 191) OMe H

H

A 157 (Example 192) OMe H

H

A 158 (Example 193) OMe H

H

A 159 (Example 195) OMe H

H

A 160 (Example 196) OMe H

H

A 161 (Example 197) OMe H

H

A 162 (Example 198) OMe H

H

A 163 (Example 199) OMe H

H

A 164 (Example 200) OMe H

H

A 165 (Example 201) OMe H

H

A 166 (Example 209) F H

H

A 167 (Example 210) F H

H

A 168 (Example 211) F H

H

A 169 (Example 212) F H

H

A 170 (Example 213) F H

H

A 171 (Example 214) F H

H

A 172 (Example 215) F H

H

A 173 (Example 216) F H

H

A 174 (Example 217) F H

H

A 175 (Example 218) F H

H

A 176 (Example 219) F H

H

A 177 (Example 220) F H

H

A 178 (Example 221) F H

H

A 179 (Example 222) F H

H

A 180 (Example 223) OMe H

H

A 181 (Example 224) OMe H

H

A 182 (Example 225) OMe H

H

A 183 (Example 226) OMe H

H

A 185 (Example 240) OMe H

H

A 186 (Example 247) OMe H

H

A 187 (Example 248) OMe H

H

A 188 (Example 249) OMe H

H

A 189 (Example 250) OMe H

H

A 190 (Example 251) OMe H

H

A 191 (Example 252) OMe H

H

A 192 (Example 264) OMe H

H

A 193 (Example 273) OMe H

H

A 194 (Example 274) OMe H

H

A 195 (Example 275) OMe H

H

A 196 (Example 276) OMe H

H

A 197 (Example 277) OMe H

H

A 198 (Example 278) OMe H

H

A 199 (Example 279) OMe H

H

A 200 (Example 280) OMe H

H

A 201 (Example 281) OMe H

H

A 202 (Example 282) OMe H

H

A 203 (Example 283) OMe H

H

A 204 (Example 284) OMe H

H

A 205 (Example 285) OMe H

H

A 206 (Example 286) OMe H

H

A 207 (Example 287) OMe H

H

A 208 (Example 288) OMe H

H

A 209 (Example 289) OMe H

H

A 210 (Example 290) OMe H

H

A 211 (Example 291) OMe H

H

A 212 (Example 292) OMe H

H

A 213 (Example 293) OMe H

H

A 214 (Example 294) OMe H

H

A 215 (Example 295) OMe H

H

A 216 (Example 296) OMe H

H

A 217 (Example 297) OMe H

(R)—Me

A 218 (Example 298) F H

H

A 219 (Example 299) F H

H

A 220 (Example 300) F H

H

A 221 (Example 301) F H

H

A 222 (Example 303) F H

H

A 223 (Example 304) F H

H

A 223 (Example 305) F H

H

A 224 (Example 306) F H

H

A 225 (Example 307) F H

H

A 226 (Example 308) F H

H

A 227 (Example 309) F H

H

A 228 (Example 310) F H

H

A 229 (Example 311) F H

H

A 230 (Example 312) F H

H

A 231 (Example 313) F H

H

A 232 (Example 316) MeO H

H

A 233 (Example 318) MeO H

H

A 234 (Example 319) MeO H

H

A 234 (Example 321) MeO H

H

A 235 (Example 323) MeO H

H

A 236 (Example 325) MeO H

H

A 237 (Example 327) MeO H

H

A 238 (Example 329) MeO H

H

A 239 (Example 330) MeO H

H

A 240 (Example 331) MeO H

H

B 241 (Example 342) MeO H

H

A 242 (Example 341) MeO H

H

C 243 (Example 343) OMe H

H

A 244 (Example 344) OMe H

H

A 245 (Example 346) OMe H

H

A 246 (Example 349) OMe H

H

A 247 (Example 351) OMe H

H

A

TABLE 2-1

EC₅₀ Table Entry Group (Example from Number.) R2 R3 R4 R A Table 1  1(Example 194) OMe H

Me

A  2 (Example 227) OMe H

(R)—Me

A  3 (Example 228) OMe H

(S)—Me

A  4 (Example 229) OMe H

Et

A  5 (Example 230) OMe H

(R)—Me

A  6 (Example 231) OMe H

(R)—Me

A  7 (Example 232) OMe H

(R)—Me

A  7 (Example 233) OMe H

(R)—Me

A  8 (Example 234) OMe H

(R)—Me

A  8 (Example 235) OMe H

(R)—Me

A  9 (Example 236) OMe H

(R)—Me

A 10 (Example 237) OMe H

(R)—Me

A 11 (Example 238) OMe H

(R)—Me

A 12 (Example 239) OMe H

(R)—Me

A 13 (Example 241) OMe H

(R)—Me

A 14 (Example 242) OMe H

(R)—Me

A 15 (Example 243) OMe H

(R)—Me

A 16 (Example 244) OMe H

(R)—Me

A 17 (Example 245) OMe H

(R)—Me

A 18 (Example 246) OMe H

(R)—Me

A 19 (Example 253) OMe H

(R)—Me

A 20 (Example 254) OMe H

(R)—Me

A 21 (Example 255) OMe H

(R)—Me

A 22 (Example 256) OMe H

(R)—Me

A 23 (Example 257) OMe H

(R)—Me

A 24 (Example 258) OMe H

(R)—Me

A 25 (Example 259) OMe H

(R)—Me

A 26 (Example 260) OMe H

(R)—Me

A 27 (Example 261) OMe H

(R)—Me

A 28 (Example 262) OMe H

(R)—Me

A 29 (Example 263) OMe H

(R)—Me

A 30 (Example 265) OMe H

(R)—Me

A 31 (Example 266) OMe H

(R)—Me

A 32 (Example 267) OMe H

(R)—Me

A 33 (Example 268) OMe H

(R)—Me

A 34 (Example 269) OMe H

(R)—Me

A 35 (Example 270) OMe H

(R)—Me

A 36 (Example 271) OMe H

(R)—Me

A 37 (Example 272) OMe H

(R)—Me

A 38 (Example 314) F H

(R)—Me

A 39 (Example 315) F H

(R)—Me

A 40 (Example 317) OMe H

(R)—Me

A 41 (Example 322) MeO H

(R)—Me

A 42 (Example 324) MeO H

(R)—Me

A 43 (Example 326) MeO H

(R)—Me

A 44 (Example 328) MeO H

(R)—Me

A 45 (Example 334) MeO H

(R)—Me

A 46 (Example 335) MeO H

(R)—Me

A 47 (Example 336) MeO H

(R)—Me

A 48 (Example 337) MeO H

(R)—Me

A 49 (Example 338) MeO H

(R)—Me

A 50 (Example 339) MeO H

(R)—Me

A 51 (Example 340) MeO H

(R)—Me

A 52 (Example 341) MeO H

(R)—Me

A 53 (Example 345) MeO H

(R)—Me

A 54 (Example 347) MeO H

(R)—Me

A 55 (Example 348) MeO H

(R)—Me

A 56 (Example 350) MeO H

(R)—Me

A 57 (Example 352) MeO H

(S)—Me

A

TABLE 3 Example 56

Table Entry EC₅₀ (Ex- Group ample from Num- Table ber) R2 R3 R4 R9 A 1 1(Ex- ample 56) H H

CH₃

B

TABLE 4

EC₅₀ Table Entry Group (Example from No.) R2 R3 R4 R9 A Table 1  1(Example 65) H H

H

A  2 (Example 66) H H

(S)—CH₃

A  3 (Example 67) H H

(R)—Me

A  4 (Example 57) H H

(R)—Me

A  6 (Example 64) Cl H

(R)—Me

A  7 (Example 58) Cl H

(R)—Me

A  8 (Example 60) Cl H

(R)—Me

A  9 (Example 61) Cl H

(R)—Me

A 10 (Example 62) Cl H

(R)—Me

A 11 (Example 63) Cl H

(R)—Me

A 12 13 (Example 51) H H

(R)—Me

A 14 (Example 52) H H

(R)—Me

A 15 (Example 53) H H

(R)—Me

A 16 (Example 54) H H

(R)—Me

A 17 (Example 86) H H

(R)—Me

A 18 (Example 126) H H

(R)—Me

A 19 (Example 127) H H

(R)—Me

A 20 (Example 128) H H

(R)—Me

A 21 (Example 129) H H

(R)—Me

A 22 (Example 130) H H

(R)—Me

A 23 (Example 131) H H

H

A 24 (Example 132) H H

H

A 25 (Example 133) H H

H

A 26 (Example 134) H H

H

A 27 (Example 135) H H

(R)—Me

A 28 (Example 136) H H

(R)—Me

A 29 (Example 137) H H

(R)—Me

A 30 (Example 158) H H

H

A 31 (Example 159) H H

H

A 32 (Example 160) H H

H

A 33 (Example 161) H H

H

A 34 (Example 202) H H

H

A 35 (Example 203) H H

H

A 36 (Example 204) H H

H

A 37 (Example 168) H H

H

A 38 (Example 205) H H

H

A 39 (Example 206) H H

H

A 40 (Example 207) H H

H

A 41 (Example 208) H H

H

A

TABLE 4-1

EC₅₀ Table Entry Group (Example from No.) R2 R3 R4 R9 A Table 1  1(Example 353) H H

H

A  2 (Example 354) H H

(S)—CH₃

A  3 (Example 355 H H

(R)—Me

A  4 Example (356) H H

(R)—Me

A  6 (Example 357) Cl H

(R)—Me

A  7 (Example 358) Cl H

(R)—Me

A  8 (Example 359) Cl H

(R)—Me

A  9 (Example 360) Cl H

(R)—Me

A 10 (Example 361) Cl H

(R)—Me

A

Method for Extrapolating % Inhibition at 10 μM

The compounds of Table 5 below were all found to be very potent in theassay described above using % inhibition as a criteria. In Table 5, X₂,X₄ etc. indicates the point of attachment. The vast majority of thecompounds exhibited greater than 98% inhibition at a concentration of 10uM. The data at 10 μM was calculated in the following manner:

Method for Extrapolating % Inhibition at 10 μM

The data in Table 5 was obtained using the general procedures above andby the following methods. Data is not reported for all compounds sincedata for all the compounds is reported by the alternate method in theprevious Tables 1-4. The percent inhibition for each compound wascalculated by quantifying the level of luciferase expression in cellsinfected in the presence of compound as a percentage of that observedfor cells infected in the absence of compound and subtracting such adetermined value from 100. For compounds tested at concentrations lessthan 1011M, the percent inhibition at 10 μM was determined byextrapolation using the XLfit curve fitting feature of the MicrosoftExcel spreadsheet software. Curves were obtained from 10 data points (%inhibition determined at 10 concentrations of compound) by using a fourparameter logistic model (XLfit model 205: y=A+((B−A)/(1+((C/x)^(D)))),where, A=minimum y, B=maximum y, C=logEC₅₀, D=slope factor, and x and yare known data values. Extrapolations were performed with the A and Bparameters unlocked.

Thus the compounds of this invention are all potent antiviral inhibitorsbased on this assay.

TABLE 5 Compound # Average % inhibition at 10 μM Precursor 8 85% Example1 56%

Other Compounds of the Invention:

The 5-aza inhibitors shown in Table 6 should also be active antiviralagents. They are also part of the invention and could be prepared fromprecursors 1a or 2s or the corresponding 7-desbromo-7-chloro precursorswhich are prepared analogously and the methods herein or by using othermethods described herein.

TABLE 6

Table Entry (Example Number.) R2 R3 R4 R9 A 1 MeO H

H

2 MeO H

H

3 MeO H

H

4 MeO H

H

The compounds in the following Tables exemplify without restriction someof the many additional inhibitors which could be prepared by usingmethodology contained herein or exemplified in the preparation of thecompounds of the invention.

TABLE 2a

R2 R3 R4 R9 A OMe H

H

F H

H

Cl H

H

F H

H

OMe H

H

OMe H

H

F H

H

F H

H

F H

H

OMe H

H

F H

H

Cl H

H

Cl H

(R)—Me

F H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

H H

(R)—Me

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

F H

H

F H

H

F H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

OMe H

H

The inhibitors in Table 4a could be prepared using analogous procedureswhich were demonstrated to prepare the examples in Table 4.

TABLE 4a

Table Entry R2 R3 R4 R9 A 1 H H

H₃

2 H H

H

3 H H

H

4 H H

H

5 H H

H

6 H H

H

7 H H

H

8 H H

H

9 H H

H

R2 R3 R4 R9 A OMe H

(R) or (S) Me

F H

(R) or (S) Me

Cl H

(R) or (S) Me

F H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

F H

(R) or (S) Me

F H

(R) or (S) Me

F H

(R) or (S) Me

OMe H

(R) or (S) Me

F H

(R) or (S) Me

Cl H

(R) or (S) Me

Cl H

(R) or (S) Me

F H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

H H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

F H

(R) or (S) Me

F H

(R) or (S) Me

F H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

F H

(R) or (S) Me

F H

(R) or (S) Me

F H

(R) or (S) Me

F H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

OMe H

(R) or (S) Me

R4 R9 A

(R) or (S) Me

(R) or (S) Me

(R) or (S) Me

(R) or (S) Me

(R) or (S) Me

(R) or (S) Me

(R) or (S) Me

(R) or (S) Me

Metabolic Stability Studies of Compounds in Liver Microsomes.

The metabolic stability of compounds were investigated in pooled livermicrosomes from humans. The human liver microsomes were obtained from BDGentest (Lot #16, Woburn, Mass.) with a protein concentration of 20mg/ml and a total cytochrome P450 (CYP) concentration of 0.55 nmol/mgprotein.

A stock solution of drug was prepared in acetonitrile at 1 mM. Analiquot of the stock solution was added to the incubation media to givea final concentration of 3 μM of drug, and the acetonitrileconcentration not exceeding 1% in the incubation. The incubation mediaconsisted of potassium phosphate buffer (0.1 M, pH 7.4), livermicrosomes (final concentration 0.9 mg/ml), magnesium chloride (0.033mM), and a NADPH-regenerating system. The cofactors of theNADPH-regenerating system consisted of NADPH (final concentration 0.425mg/ml), glucose-6-phosphate (final concentration 0.512 mg/ml), andglucose-6-phosphate dehydrogenase (final concentration 0.6 unit/ml). Thetest compound was pre-incubated in the media for 2 min. The reaction wasinitiated by the addition of the cofactors. The incubation was carriedout at 37° C. for 10 min. The reaction was terminated by drawing analiquot of 100 μl, from the incubation and adding into 200 μL ofacetonitrile containing a reference compound as an external analyticalstandard. Following vortex-mixing and centrifugation, an aliquot of 10μL of the supernatant was analyzed by LC/MS.

GUIDELINES can be used to categorized test substances as low,intermediate or highly cleared compounds.

Rate Clearance (nmol/min/mg) Estimate    0-0.100 Low 0.101-0.200Intermediate 0.201-0.300 High

Rat Pharmacokinetic Studies:

For the IV and PO pharmacokinetic studies of compounds in rats, thecompound was dissolved in PEG-400/ethanol (90/10) as a solution.

Rat.

Male Sprague-Dawley rats (300-350 g, Hilltop Lab Animals, Inc.,Scottdale, Pa.) with cannulas implanted in the jugular vein were used.The rats were fasted overnight in the PO pharmacokinetic studies. Bloodsamples of 0.3 ml were collected from the jugular vein inEDTA-containing microtainer tubes (Becton Dickinson, Franklin Lakes,N.J.), and centrifuged to separate plasma.

In the IV study, the test compound was delivered at 1 mg/kg as a bolusover 0 5 min (n=3). Serial blood samples were collected before dosingand 2, 10, 15, 30, 45, 60, 120, 240, 360, 480, and 1440 min afterdosing.

In the PO study of the test compound, the rats (n=3) received an oraldose of 5 mg/kg of BMS-585248. Serial blood samples were collectedbefore dosing and 15, 30, 45, 60, 120, 240, 360, 480, and 1440 min afterdosing.

Quantitation of Compounds in Plasma.

Aliquots of plasma samples from rat, studies were prepared for analysisby precipitating plasma proteins with two volumes of acetonitrilecontaining an internal standard of a similar compound. The resultingsupernates were separated from the precipitated proteins bycentrifugation for 10 minutes and transferred to autosampler vials.Samples were either prepared manually, or with the use of the Tomtecautomated liquid handler. An aliquot of 5 μL was injected for analysis.

The HPLC system consisted of two Shimadzu LC1OAD pumps (Columbia, Md.),a Shimadzu SIL-HTC autosampler (Columbia, Md.), and a Hewlett PackardSeries 1100 column compartment (Palo Alto, Calif.). The column was a YMCPro C18 (2.0×50 mm, 3 μm particles, Waters Co., Milford, Mass.),maintained at 60° C. and a flow rate of 0.3 ml/min. The mobile phaseconsisted of 10 mM ammonium formate and 0.1% formic acid in water (A)and 100% 10 mM ammonium formate and 0.1% formic acid in methanol (B).The initial mobile phase composition was 95% A. After sample injection,the mobile phase was changed to 15% A/85% B over 2 minutes and held atthat composition for an additional 1 minute. The mobile phase was thenreturned to initial conditions and the column re-equilibrated for 1minute. Total analysis time was 4 minutes.

The HPLC was interfaced to a Micromass Quattro LC. Ultra high puritynitrogen was used as the nebulizing and desolvation gas at flow rates of100 L/hr for nebulization and 1100 L/hr for desolvation. The desolvationtemperature was 300° C. and the source temperature was 150° C. Dataacquisition utilized selected reaction monitoring (SRM). Ionsrepresenting the (M+H)⁺ species for the compound and the internalstandard were selected in MS1 and collisionally dissociated with argonat a pressure of 2×10⁻³ torr to form specific product ions which weresubsequently monitored by MS2.

The compounds of the present invention may be administered orally,parenterally (including subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques), byinhalation spray, or rectally, in dosage unit formulations containingconventional non-toxic pharmaceutically-acceptable carriers, adjuvantsand vehicles.

Thus, in accordance with the present invention there is further provideda method of treating and a pharmaceutical composition for treating viralinfections such as HIV infection and AIDS. The treatment involvesadministering to a patient in need of such treatment a pharmaceuticalcomposition comprising a pharmaceutical carrier and atherapeutically-effective amount of a compound of the present invention.

The pharmaceutical composition may be in the form oforally-administrable suspensions or tablets; nasal sprays, sterileinjectable preparations, for example, as sterile injectable aqueous oroleagenous suspensions or suppositories.

When administered orally as a suspension, these compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may contain microcrystalline cellulose for impartingbulk, alginic acid or sodium alginate as a suspending agent,methylcellulose as a viscosity enhancer, and sweetners/flavoring agentsknown in the art. As immediate release tablets, these compositions maycontain microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants known in the art.

The injectable solutions or suspensions may be formulated according toknown art, using suitable non-toxic, parenterally-acceptable diluents orsolvents, such as mannitol, 1,3-butanediol, water, Ringer's solution orisotonic sodium chloride solution, or suitable dispersing or wetting andsuspending agents, such as sterile, bland, fixed oils, includingsynthetic mono- or diglycerides, and fatty acids, including oleic acid.

The compounds of this invention can be administered orally to humans ina dosage range of 1 to 100 mg/kg body weight in divided doses. Onepreferred dosage range is 1 to 10 mg/kg body weight orally in divideddoses. Another preferred dosage range is 1 to 20 mg/kg body weightorally in divided doses. It will be understood, however, that thespecific dose level and frequency of dosage for any particular patientmay be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular condition, and the hostundergoing therapy.

Scheme 41a depicts methodology for converting a carboxylic acid to analkynyl ketone. The alkynyl ketone precursors can then be converted topyrazoles or isoxazoles upon reaction with hydrazines or hydroxylamines, respectively.

The invention is intended to cover isomers, diasteroisomers,stereoisomers, and enantiomers of the depicted formulas when one or moreasymmetric carbons are present in the molecules. An asymmetric carbon isone in which the carbon is attached to four different substitutions. Inparticular, the invention is intended to cover isomers or a singleenantiomer especially when one enantiomer displays superior properties.Enantiomers differ from one another in that the spacial arrangement ofthe substituents around the chiral centers of the asymmetric carbonsresult in each molecule being a nonsuperimposable mirror image of theother. In this application, the configuration of the substituents aroundan asymmetric carbon are defined unambiguously as either (R) which is astandard representation which stands for Latin rectus, right or (S)which is the standard representation for Latin sinister, left in theCahn-Ingold-Prelog nomenclature system which has been in use since the1960s. Standard rules for defining the configuration of these centersare found in any basic organic chemistry textbook. In particular, forthis application and based on initial examples, when W contains a singlemethyl group as depicted below, when the carbon bearing the methyl groupis in the (R) configuration it may show a potency advantage over the (S)enantiomer. Occasionally the (R)-methyl piperazine may show a potencyadvantage over the unsubstituted piperazine. These observations arecompound specific effect and are not always present. The unsubstitutedpiperazine and (S) enantiomers are still potent antiviral compoundsdespite occasionally being less potent than the (R) enantiomer.

When the configuration of a methyl piperazine shown as below is (R) themethyl group may improve the metabolic stability of the adjacent amideas compared to the (S) methyl piperazine or the unsubstitutedpiperazine. However, the metabolic stability of the amide bond iscompound specific and a methyl substituent is not necessarily requiredfor optimal properties.

It has now also been surprisingly found that compounds of Formula Ia, inwhich specifically R₄ is an N-linked triazolyl group, attached at the1-nitrogen position, are particularly effective for inhibiting HIV. Thisis discussed more fully below.

The effective treatment of HIV and other viruses requires compounds thatare potent inhibitors of the virus, are selective for the virus, andhave the properties which allow them to safely achieve and maintainplasma level concentrations which are a maximum number multiples abovethe concentration required to minimally inhibit the virus. Higherexposures suppress viral replication and reduced rates of replicationmean that strains of virus with resistance to the drug treatment willdevelop at a slower rate. Potent drugs exhibit equivalent activity froma lower concentration or lower dose than that needed to achieve the sameeffect from a less potent drug. Drugs which intrinsically produce higherexposures from an equivalent dose in animal models or patients (asdetermined by pharmacokinetic measurements such as AUC (the sum of theconcentration of drug over a particular time), Cmax, or Cmin will alsoprovide greater benefit to the patient. Drugs which have higherstability in the presence of metabolizing pathways and enzymes willmaintain their concentrations longer and thus require less frequentdosing or dosing of smaller quantities. In animals or people the rate ofclearance is a frequently measured parameter to assess this property butmean retention time is also used. For accuracy, the determined measureof viral inhibition is an EC50; but the minimum plasma concentrationswhich should be maintained in a patient is generally believed to be atleast four or five fold higher. Thus the antiviral or anti HIV drugcandidates which will be most likely to provide maximum benefits inpatients and those that preclinical research programs strive to identifywill exhibit 1) maximum potency 2) no general cytotoxicity vs the cellline used for the assay 3) low predicted rates of metabolism in humanbased on in vitro models 4) high exposure after oral dosing. Many otherproperties of potential drug candidates are evaluated in order todetermine which compounds will have the best chance of showing optimalutility in human patients but the compounds of this invention wereevaluated initially in part by determining:

1) Potency vs HIV as determined by an EC50 in an initial pseudotypeassay as described in the biology section.2) Lack of general cytotoxicity vs a Hela cell line. >100 uM was used asan arbitrary cut off for safety.3) Measurement of the rate of metabolism vs human liver microsomalpreparations and from this data projecting human rate of clearance.Lower is better.4) Estimating potential exposure in man by measuring parameters such asAUC and rate of clearance by oral and iv dosing in rats. High exposureand low clearance was desired.

Aazaindole oxoacetic piperazine amides have been disclosed in two seriesof patent applications. The first series discloses azaindole derivativeswhich have promising potential as antiviral agents (hereinafter called,reference 94) Wang, Tao et al, U.S. Pat. No. 6,476,034 and WO 0162255A1, filed Jan. 19, 2001, published Aug. 30, 2001. The second series(hereinafter called, reference 106) Wang, Tao, et al discloses HIVAntiviral Activity of Substituted Azaindoleoxoacetic PiperazineDerivatives in U.S. patent application Ser. No. 10/214,982 filed Aug. 7,2002, which is a continuation-in-part application of U.S. Ser. No.10/038,306 filed Jan. 2, 2002 (corresponding to PCT Int. Appl.(PCT/US02/00455), WO 02/062423 A1, filed Jan. 2, 2002, published Aug.15, 2002. All of the references for these two series are incorporated byreference herein. Reference 106 describes in part C-7 heteroaryl, arylor substituted 4,5,6, or 7-azaindoles as antiviral agents and is themost relevant prior art.

We have evaluated the properties of many compounds covered within thescope of references 94 and 106 and have found that the compounds havingC-7, N-linked triazole groups are surprisingly and unexpectedlysuperior.

We initially evaluated compounds to determine which showed maximumpotency or the lowest EC50 using the pseudotype assay described in thebiology section of this application. In our case compounds with EC50sless than 0.20 nM were considered of most interest since this coveredthe most potent compounds and accounted for assay variability of ourinitial screen. The stability of compounds were also evaluated todetermine metabolic stability when incubated in in vitro preparations ofhuman liver microsomes (HLM). This is one commonly used predictivesystem for evaluating the potential for human metabolism and projectingclearance rates in man. Compounds with low clearance rates were mostdesireable. Intermediate and high clearance compounds would be morelikely to have difficulty achieving feasible dosing regimen's in man vslow clearance compounds. Compounds for which accurate determinationscould not be made were also not advanced.

Surprisingly, when the most promising compounds from the potency andmetabolic stability criterias were evaluated in rats to measure theirpharmacokinetic properties, one class of C-7 substituents, N linkedtriazoles of Formula Ia showed very low clearance and very high AUCs(exposure) when compared to the compounds of references 94 and 106.

The compounds I having Formula Ia are described below:

wherein:R² is methoxy, fluoro or chloro;

R⁴ is

D is hydrogen or C₁-C₃ alkyl;E is selected from the group consisting of hydrogen, (C₁-C₃)alkyl,O(C₁-C₃)alkyl or CH₂OCH₃.R¹¹ is either hydrogen or methyl in which the configuration to which themethyl is attached is (R) with the proviso that when R⁴ is1,2,3-triazole, then R¹¹ is hydrogen.

The C-7 N-linked triazoles thus showed surprising properties as theywere essentially equivalent in potency to the most potent compoundscovered by references 94 and 106 that we have evaluated to date. Theyshowed metabolic stability in human liver microsomes that was equivalentto the best compounds from the application. Unexpectedly, they showedclearance rates in rats that were much lower, usually 10 fold lower thanthe best compounds from those described in the applications of reference94 and were the best of any compounds evaluated in reference 106. Evenmore surprisingly, they were the only class of compounds to showsignificantly increased exposure in rats as shown by their AUCs.

In summation, these N-linked triazoles exhibited a surprisingcombination of properties that would not be obvious to one skilled inthe art relying on the disclosure of references 94 and 106. Only asingle triazole is disclosed in WO 02/06423. This compound has an R⁴substiuent which is a C-linked triazole, and not an N-linked triazole,and exhibited potency which was not comparable to the N-linkedtriazoles. No N-linked triazoles were described in the examples of thepublished PCT application from reference 106.

The following data tables summarize the potency, predicted humanclearance based on human liver microsomes, and the AUC and clearancedetermined by pharmacokinetic studies in rats for these N-linkedtriazoles of the invention herein compared with representative compoundsand close analogs contained in PCT application WO 02/062423 A1, filedJan. 2, 2002, published Aug. 15, 2002 and the published applications andpatents contained in reference 94. As seen in the following tables the Nlinked triazoles herein identified as most preferred groups exhibitsurprising superiority especially in terms of displaying maximumpotency, metabolic stability equivalent to best in class and uniquely ahigh AUC (exposure) and low clearance in rats which is determined byoral and iv dosing at 5 mg/kg and 1 mg/kg respectively. The rat model isan initial model used to assess potential for exposure in man.

The utility of compounds in the triazole class is surprisingly verydependent on the substitution patterns as depicted. For example the1,2,3 triazoles attached at the 2-position nitrogen atom have to dateshown significantly reduced AUC (exposure) in rats compared to thecompounds depicted. In addition, moving the E group when E is methyl, inthe 1,2,4-N-linked triazole from position 3 to 5 provides compounds withsignificantly reduced potency. As can be seen in Table A2, the N-linkedtriazoles specified showed high potency in an initial antiviral assay.

As evidenced by Tables A3-A8 of Comparator compounds, the metabolicstability of the N-linked triazole compounds Ia of the invention issurprisingly equivalent to or better than any of the compounds coveredin either series of published azaindole applications (i.e. references 94and 106).

As dramatically shown in the tables, the low clearance and high exposureseen in rats for the compounds in table A2 was surprising and unexpectedsince the prior art taught compounds did not exhibit these properties asone would have expected.

In the tables that follow these terms have the following in meanings:

“NT” meant not tested.“Difficulties” means results could not be interpreted (i.e. in HLMtest).

Results

TABLE A1 Biological Data Key for EC₅₀s in Tables A2-A7 Compounds*Compounds Compounds with with EC₅₀s > with EC₅₀s > 0.2 nM EC50 ≦ 1 μMbut < 1 μM 0.20 nm Group 3 Group 2 Group 1

TABLE A2 N linked Triazoles as R4 with Surprising Superior PropertiesHLM predicted human Example EC50 CC50 > clearance AUC 24 h CL, iv Numbercategory 100 uM class (ug · hr/mL) (mL/min/kg) 216 1 Yes Low  32 ± 121.6 ± 0.2 188 1 Yes Low   20 ± 4.6  2.4 ± 0.08 187 1 Yes Low 22.4 ± 7.22.4 ± 0.5 215, 303 1 Yes Low 83.7 ± 9.8  0.7 ± 0.12 245 1 Yes Low 12.1 ±1.3 5.6 ± 1.8 313 1 Yes Low 316 1 Yes Low   52 ± 12  1.3 ± 0.19 317 1Yes Low   43 ± 12  1.9 ± 0.26 306 1 Yes Low  160 ± 11 0.39 ± 0.07 321 1Yes Low 322 1 Yes Low   82 ± 23 1.8 ± 0.4 314 1 Yes Low 315 1 Yes Low352 1 Yes Low 325 1 Yes Low 326 1 Yes Low  9.8 ± 2.9 8.3 274 1 Yes Low273 1 Yes Low 324 1 Yes Low 275 1 Yes Low

TABLE A3 Some Other Alternatively Substituted N linked Triazoles at R4as Comparators HLM predicted human Example EC50 CC50 > clearance AUC 24hCL, iv Number category 100 uM class (ug.hr/mL) (mL/min/kg) 217 2 Yes NTNT NT 307 2 Yes NT NT NT 256 2 Yes NT NT NT 350 2 Yes Low NT NT 327 2Yes Low NT NT 328 1 Yes Low NT NT 351 NT NT Low 1.5 ± 0.14 16.6 ± 1.4

TABLE A4 Some Other Relevant N linked Heteroaryls at R4 as ComparatorsHLM predicted human Example EC50 CC50 > clearance AUC 24 h CL, iv Numbercategory 100 uM class (ug · hr/mL) (mL/min/kg) 139 2 Yes High 219, 305 1Yes High 193 1 No Low 14 ± 8   4.5 ± 0.4 189 2 Yes Low 222 2 Yes Low 2212 Yes Low 220 2 Yes NT 218, 304 2 Yes Low 190 1 Yes Low  7.4 ± 3.4*  3.7± 1.0 191 2 Yes NT 309 1 Yes Low 0.09 ± 0.05 34.3 ± 2.6 318 2 Yes Low310 1 Yes Low  2.1 ± 0.4* 16.5 ± 3.3 241 1 Yes Low  6.4 ± 4.2* 11.2 ±0.9 312 2 Yes Low 241 1 Yes Low 0.0086 ±  131 ± 4.3 0.005 ** 236 1 YesLow 0.56 ± 0.25   29 ± 6.7 251 1 Yes Low 230 1 Yes Intermediate 343 1Yes Low 344 2 No Low 276 1 Yes NT 255 1 Yes Intermediate 258 1 Yes Low314 1 Yes Low 315 1 Yes Low 352 1 Yes Low 326 1 Yes Low 9.8 ± 2.9 8.3274 1 Yes 273 1 Yes 275 1 Yes

TABLE A5 Some Relevant C linked Heteroaryl Comparators HLM predictedhuman Example EC50 CC50 > clearance AUC 24 h CL, iv Number category 100uM class (ug · hr/mL) (mL/min/kg) 40 2 No Low 42 2 Yes Low 22 1 NoIntermediate 35 1 Yes Intermediate 37 1 No NT 38 1 No Low 39 2 NoIntermediate 28 3 No NT 29 2 No High 22 2 No High 74 2 No Intermediate71 1 Yes Intermediate 73 1 Yes Intermediate 78 2 Yes Intermediate 94 1Yes NT 102 2 Yes Low 6.9 ± 1.3   12 ± 5.5 163 2 Yes Difficulties 95 1Yes Intermediate 140 2 Yes Intermediate 146 2 Yes Intermediate 145 1 YesDifficulties  12 ± 3.8   1.4 ± 0.29 148 2 Yes NT 210 1 Yes Intermediate211 1 No Intermediate 212 1 Yes Low 223 2 Yes Low 224 2 Yes Low 225 2Yes NT 227 2 Yes Low  3.8 ± 0.83  8.8 ± 3.7 226 1 Yes Low   0.5 ± 0.13*24.5 ± 3   299 1 No Low 300 2 Yes Low 266 1 Yes Low  0.16 ± 0.04* 37.4 ±3.2 345 2 Yes Low 301 2 Yes NT 346 2 Yes NT 347 2 Yes Low 334 2 Yes NT348 2 Yes Low 349 2 Yes NT 342 1 Yes Low

TABLE A6 Some Relevant 4-azaindole Comparators and data HLM predictedhuman Example EC50 CC50 > clearance AUC 24 h CL, iv Number category 100uM class (ug · hr/mL) (mL/min/kg) 204 2 Yes Low   12 ± 1.4   10 ± 1.3161 1 Yes High 205 2 Yes Low  9.6 ± 1.2  5.4 ± 0.4 207 2 Yes Low 206 2Yes NT 208 2 Yes NT 353 2 Yes Low  1363 ± 307   5.6 ± 1.1* 354 2 Yes Low1.26 11.2 ± 0.8 0.18* 355 2 Yes Low    3.3 ± 0.77* 13.9 ± 5.3 356 2 YesLow 357 2 Yes Intermediate 358 2 Yes High 359 2 Yes NT 360 2 Yes Low 3612 Yes NT

TABLE A7 Some Relevant Comparators and data from U.S. Pat. No. 6,476,034(Reference 94) HLM predicted Reference human Compound EC50 CC50 >clearance AUC 24 h CL, iv Number category 100 uM? class (ug · hr/mL)(mL/min/kg) 1 2 Yes Low 0.5  32 ± 1.8 2 2 Yes Intermediate 3 2 Yes Low6.3 ± 2.7   13 ± 4.0 4 2 Yes Low 5 1 Yes Intermediate 6 2 Yes Low 1.7 ±0.58  31 ± 5.9 7 1 Yes Low  2.6 ± 0.12* 19.3 ± 0.65 8 1 Yes Low 1.03 ±0.07* 47.2 ± 11.5 9 2 Yes Low 5.9 ± 2.2  5.9 ± 2.2 10 2 Yes Low 2.9 ±0.3  11.7 ± 1.0  11 1 Yes 1.4 ± 0.2* 24.8 ± 0.41 12 1 Yes Low 4.7 ± 1.1 11.9 ± 1.8  13 2 Yes NT

Structures of Reference Compounds as a Key for Table A7 ReferenceCompound 1

TABLE A8 (Reference compounds structures 2-9)

Ref- erence Com- pound Num- ber R2 R3 R4 R9 A 2 OMe H X₂—OMe (R)—Me

3 OMe H X₂—OMe H

4 OMe H X₂—OH H

5 Cl H

H

6 F H

H

7 F H

H

8 MeO H

H

9 MeO H

H

TABLE A9 (Reference compounds 10-12)

Ref- erence Com- pound Num- ber R2 R3 R4 R11 A 10 MeO H X₂—OMe (R)—Me

11 MeO H

(R)—Me

12 MeO H

(R)—Me

In Tables A8 and A9, X₂ and X₄ refer to point of attachment.

What is claimed is:
 1. A prodrug of the compound having the followingformula: